Extracellular vesicles in tumorigenesis, metastasis, chemotherapy resistance and intercellular communication in osteosarcoma

Figures & data

Figure 1. Secretion of extracellular vesicles (EVs) and their contents. EVs are originally derived from the endosomal and lysosomal pathway. EVs contain a range of proteins, RNAs, mRnas, DNA molecular cargoes, and surface protein markers. They can be released by any type of cells and can be transferred from the original cell to the recipient cells, into the extracellular microenvironment or to a distant site.

Figure 2. Functions of tumor-derived extracellular vesicles (EVs) in osteosarcoma progression and microenvironment. Firstly, tumor-derived EVs promote osteosarcoma tumorigenesis, and induce drug resistance through delivering multiple proteins, miRnas, and lncRnas to the recipient cancer cells. Secondly, tumor-derived EVs regulate the functions of endothelial cells and cancer-associated fibroblasts to promote angiogenesis and metastasis. Lastly, tumor-derived EVs also have significantly roles in osteoclastogenesis, inflammation regulation, and immunomodulation.

Table 1. Overview of exosomal cargoes and functions of tumor-derived EVs.

Evs sources	Recipient cells	EVs cargos	Functions	Reference
Tumor cells	Tumor cells	hsa_circ_103801	Reduced the sensitivity of osteosarcoma cells to CDDP	[25]
Tumor cells	Tumor cells	LincTRNA-00852	Promoted proliferation, migration, and invasion	[26]
Tumor cells	Tumor cells	miR-1307	Promoted the proliferation, migration, and invasion	[27]
Tumor cells	Tumor cells	Hic-5	Inhibited apoptosis and increased proliferation	[28]
Tumor cells	Tumor cells	LncRNA OIP5-AS1	Promoted the angiogenesis	[29]
Tumor cells	Tumor cells	PDL-1, N-cadherin	Promoted pulmonary metastasis	[30]
Tumor cells	Tumor cells	lncRNA-ANCR	Induced drug resistance	[31]
Tumor cells	Tumor cells	miR-675	Promoted cell migration and invasion	[32]
Tumor cells	MSCs	-	Promoted bone microenvironment remolding	[33]
Tumor cells	MSCs	Transforming growth factor-β(TGF-β)	Promoted IL-6 release	[34]
Tumor cells	Tumor cells, Macrophages	PYK2, Rab22a-NeoF1	M2 type differentiation of macrophages and tumor lung metastasis	[35]
Tumor cells	Macrophages	-	Promoted the M2 phenotype and created an immunosuppressive, tumor-promoting microenvironment	[36]
Tumor cells	Macrophages	Tim-3	Induced M2 macrophage polarization and promoted the metastasis of osteosarcoma cells	[37]
Tumor cells	T cells	PD-L1	Induced immunosuppression	[38]
Tumor cells	BMDMs	miR-501-3p	Promotes osteoclastogenesis, aggravates bone loss	[39]
Tumor cells	Fibroblasts	COL6A1	Promote osteosarcoma cell invasion and migration	[40]
Tumor cells	HUVECs	miR-199a-5p	Inhibited tumorigenesis and angiogenesis	[41]
Tumor cells	Vascular endothelial cells	LncRNA-EWSAT1	Induced increase in angiogenic factor secretion and angiogenesis	[42]
Tumor cells	Endothelial cells	miRNAs	Potentiated tube formation, increased angiogenic markers expression	[43]
Tumor cells	Vascular endothelial cells	miR-25-3p	Promoted capillary formation	[44]

Figure 3. The regulatory network of microenvironment-derived extracellular vesicles (EVs) in osteosarcoma. EVs secreted in the plasma, immune cells, osteoclasts, chondrocytes, cancer-associated fibroblasts, and mesenchymal stem cells from different sources promoted or inhibited osteosarcoma tumorigenesis through different cargoes.

Table 2. Overview of exosomal cargoes and roles of microenvironment-derived EVs.

Fibroblasts	Tumor cells	miR-1288	Increased migration and invasion	[69]
Fibroblasts	Tumor cells	LncRNA-SNHG17	Promoted proliferation and metastasis	[70]
MSCs	Tumor cells	miR-143	Inhibited tumor cells migration	[71]
MSCs	Tumor cells	miR-150	Suppressed proliferation and migration	[72]
MSCs	Tumor cells	-	Activated PI3K/AKT and HIF-1α signaling pathway	[73]
BMSCs	Tumor cells	miR-1913	Inhibited tumor progression	[74]
BMSCs	Tumor cells	miR-206	Inhibited tumor progression	[67]
BMSCs	Tumor cells	miR-769-5p	Promoted proliferation and metastasis	[75]
BMSCs	Tumor cells	miR-208a	Promoted proliferation, invasion and migration	[76]
BMSCs	Tumor cells	miR-21-5p	Promoted proliferation and invasion	[77]
BMSCs	Tumor cells	-	Promoted oncogenic autophagy	[78]
BMSCs	Tumor cells	(lymphocyte cytosolic protein 1) LCP1	Promoted tumorigenesis and metastasis	[79]
BMSCs	Tumor cells	lncRNA-PVT1	Promoted cell growth and metastasis	[46]
BMSCs	Tumor cells	-	Activated the hedgehog signaling	[80]
BMSCs	Tumor cells	lncRNA-NORAD	Promoted migration, invasion, and angiogenesis	[81]
BMSCs	Tumor cells	lncRNA-MALAT1	Promoted proliferation, invasion and migration	[82]
BMSCs	Tumor cells	CircNRIP1	Promoted tumor progression	[83]
ADMSCs	Tumor cells	COLGALT2	Fostered cell invasion, migration and proliferation	[84]
ADMSCs	Tumor cells	miR-101	Suppressed tumor progression	[85]
Macrophages	Tumor cells	lncRNA LIFR-AS1	Promoted proliferation, invasion, suppressed apoptosis	[86]
Macrophages	Tumor cells	miR-221-3p	Aggravated cell growth and metastasis	[87]
Plasma	Tumor cells	SENP1	-	[88]
Plasma	Tumor cells	lncRNA-CASC15	Promoted tumor progression	[89]
Plasma	Tumor cells	miR-15a	Suppressed proliferation and invasion	[78]
Osteoblast	Tumor cells	circ_0000190	Suppressed tumorigenesis	[90]
Osteoblast	Tumor cells	-	Regulated mineralization process	[91,92]
HUVECs	Tumor cells	-	Promoted the stemness of osteosarcoma cells	[93]
Chondrocyte	Tumor cells	miR-195	Inhibited proliferation and anti-apoptotic	[68]

Pan Y, Lin Y, Mi C. Cisplatin-resistant osteosarcoma cell-derived exosomes confer cisplatin resistance to recipient cells in an exosomal circ_103801-dependent manner. Cell Biol Int. 2021;45(4):858–868.

 PubMed Web of Science ®Google Scholar

Li Q, Wang X, Jiang N, et al. Exosome-transmitted linc00852 associated with receptor tyrosine kinase AXL dysregulates the proliferation and invasion of osteosarcoma. Cancer Med. 2020;9(17):6354–6366. DOI:10.1002/cam4.3303

 PubMed Web of Science ®Google Scholar

Han F, Pu P, Wang C, et al. Osteosarcoma cell-derived exosomal Mir-1307 promotes tumorgenesis via targeting AGAP1. BioMed Res Int. 2021;2021:7358153.

 PubMed Web of Science ®Google Scholar

Sha L, Ma D, Chen C. Exosome-mediated Hic-5 regulates proliferation and apoptosis of osteosarcoma via Wnt/beta-catenin signal pathway. Aging. 2020;12(23):23598–23608. DOI:10.18632/aging.103546

 PubMedGoogle Scholar

Li Y, Lin S, Xie X, et al. Highly enriched exosomal lncRNA OIP5-AS1 regulates osteosarcoma tumor angiogenesis and autophagy through miR-153 and ATG5. Am J Transl Res. 2021;13(5):4211–4223.

 PubMed Web of Science ®Google Scholar

Wang J, Zhang H, Sun X, et al. Exosomal PD-L1 and N-cadherin predict pulmonary metastasis progression for osteosarcoma patients. J Nanobiotechnology. 2020;18(1):151. DOI:10.1186/s12951-020-00710-6

 PubMed Web of Science ®Google Scholar

Hu X, Wen Y, Tan L-Y, et al. Exosomal long non-coding RNA ANCR Mediates Drug Resistance in Osteosarcoma. Front Oncol. 2021;11:735254.

 PubMed Web of Science ®Google Scholar

Gong L, Bao Q, Hu C, et al. Exosomal miR-675 from metastatic osteosarcoma promotes cell migration and invasion by targeting CALN1. Biochem Biophys Res Commun. 2018;500(2):170–176. DOI:10.1016/j.bbrc.2018.04.016

 PubMed Web of Science ®Google Scholar

Mannerstrom B, et al. Epigenetic alterations in mesenchymal stem cells by osteosarcoma-derived extracellular vesicles. Epigenetics. 2019;14(4):352–364. DOI:10.1080/15592294.2019.1585177

 PubMed Web of Science ®Google Scholar

Baglio SR, Lagerweij T, Pérez-Lanzón M, et al. Blocking Tumor-Educated MSC Paracrine Activity Halts Osteosarcoma Progression. Clin Cancer Res. 2017;23(14):3721–3733. DOI:10.1158/1078-0432.CCR-16-2726

 PubMed Web of Science ®Google Scholar

Zhong L, Liao D, Li J, et al. Rab22a-NeoF1 fusion protein promotes osteosarcoma lung metastasis through its secretion into exosomes. Signal Transduct Target Ther. 2021;6(1):59. DOI:10.1038/s41392-020-00414-1

 PubMed Web of Science ®Google Scholar

Wolf-Dennen K, Gordon N, Kleinerman ES. Exosomal communication by metastatic osteosarcoma cells modulates alveolar macrophages to an M2 tumor-promoting phenotype and inhibits tumoricidal functions. Oncoimmunology. 2020;9(1):1747677.

 PubMed Web of Science ®Google Scholar

Cheng Z, Wang L, Wu C, et al. Tumor-derived exosomes induced M2 Macrophage Polarization and Promoted the Metastasis of Osteosarcoma Cells Through Tim-3. Arch Med Res. 2021;52(2):200–210. DOI:10.1016/j.arcmed.2020.10.018

 PubMed Web of Science ®Google Scholar

Zhang L, et al. Exosomes loaded with programmed death ligand-1 promote tumor growth by immunosuppression in osteosarcoma. Bioengineered. 2021;12(2):9520–9530. DOI:10.1080/21655979.2021.1996509

 PubMed Web of Science ®Google Scholar

Lin L, Wang H, Guo W, et al. Osteosarcoma-derived exosomal miR-501-3p promotes osteoclastogenesis and aggravates bone loss. Cell Signal. 2021;82:109935.

 PubMed Web of Science ®Google Scholar

Zhang Y, et al. H3K27 acetylation activated-COL6A1 promotes osteosarcoma lung metastasis by repressing STAT1 and activating pulmonary cancer-associated fibroblasts. Theranostics. 2021;11(3):1473–1492. DOI:10.7150/thno.51245

 PubMed Web of Science ®Google Scholar

Zhang L, Cao H, Gu G, et al. Exosomal MiR-199a-5p Inhibits Tumorigenesis and Angiogenesis by Targeting VEGFA in Osteosarcoma. Front Oncol. 2022;12:884559.

 PubMed Web of Science ®Google Scholar

Tao SC, Huang J-Y, Wei Z-Y, et al. EWSAT1 Acts in Concert with Exosomes in Osteosarcoma Progression and Tumor-Induced Angiogenesis: the “Double Stacking Effect”. Adv Biosyst. 2020;4(9):e2000152. DOI:10.1002/adbi.202000152

 PubMed Web of Science ®Google Scholar

Raimondi L, et al. Osteosarcoma cell-derived exosomes affect tumor microenvironment by specific packaging of microRnas. Carcinogenesis. 2020;41(5):666–677. DOI:10.1093/carcin/bgz130

 PubMed Web of Science ®Google Scholar

Yoshida A, Fujiwara T, Uotani K, et al. Clinical and Functional Significance of Intracellular and Extracellular microRNA-25-3p in Osteosarcoma. Acta Med Okayama. 2018;72(2):165–174. DOI:10.18926/AMO/55857

 PubMed Web of Science ®Google Scholar

Wang JW, Wu X-F, Gu X-J, et al. Exosomal miR-1228 from cancer-associated fibroblasts promotes cell migration and invasion of osteosarcoma by directly targeting SCAI. Oncol Res. 2019;27(9):979–986. DOI:10.3727/096504018X15336368805108

 PubMed Web of Science ®Google Scholar

Zhao A, Zhao Z, Liu W, et al. Carcinoma-associated fibroblasts promote the proliferation and metastasis of osteosarcoma by transferring exosomal LncRNA SNHG17. Am J Transl Res. 2021;13(9):10094–10111.

 PubMed Web of Science ®Google Scholar

Shimbo K, Miyaki S, Ishitobi H, et al. Exosome-formed synthetic microRNA-143 is transferred to osteosarcoma cells and inhibits their migration. Biochem Biophys Res Commun. 2014;445(2):381–387. DOI:10.1016/j.bbrc.2014.02.007

 PubMed Web of Science ®Google Scholar

Xu Z, Zhou X, Wu J, et al. Mesenchymal stem cell-derived exosomes carrying microRNA-150 suppresses the proliferation and migration of osteosarcoma cells via targeting IGF2BP1. Transl Cancer Res. 2020;9(9):5323–5335. DOI:10.21037/tcr-20-83

 PubMed Web of Science ®Google Scholar

Lin S, Zhu B, Huang G, et al. Microvesicles derived from human bone marrow mesenchymal stem cells promote U2OS cell growth under hypoxia: the role of PI3K/AKT and HIF-1α. Hum Cell. 2019;32(1):64–74. DOI:10.1007/s13577-018-0224-z

 PubMed Web of Science ®Google Scholar

Zhou J, Xu L, Yang P, et al. The exosomal transfer of human bone marrow mesenchymal stem cell-derived miR-1913 inhibits osteosarcoma progression by targeting NRSN2. Am J Transl Res. 2021;13(9):10178–10192.

 PubMed Web of Science ®Google Scholar

Zhang H, Wang J, Ren T, et al. Bone marrow mesenchymal stem cell-derived exosomal miR-206 inhibits osteosarcoma progression by targeting TRA2B. Cancer Lett. 2020;490:54–65.

 PubMed Web of Science ®Google Scholar

Liu W, Wang B, Duan A, et al. Exosomal transfer of miR-769-5p promotes osteosarcoma proliferation and metastasis by targeting DUSP16. Cancer Cell Int. 2021;21(1):541. DOI:10.1186/s12935-021-02257-4

 PubMed Web of Science ®Google Scholar

Qin F, Tang H, Zhang Y, et al. Bone marrow-derived mesenchymal stem cell-derived exosomal microRNA-208a promotes osteosarcoma cell proliferation, migration, and invasion. J Cell Physiol. 2020;235(5):4734–4745. DOI:10.1002/jcp.29351

 PubMed Web of Science ®Google Scholar

Qi J, Zhang R, Wang Y. Exosomal miR-21-5p derived from bone marrow mesenchymal stem cells promote osteosarcoma cell proliferation and invasion by targeting PIK3R1. J Cell Mol Med. 2021;25(23):11016–11030.

 PubMed Web of Science ®Google Scholar

Wu C, Li Z, Feng G, et al. Tumor suppressing role of serum-derived exosomal microRNA-15a in osteosarcoma cells through the GATA binding protein 2/murine double minute 2 axis and the p53 signaling pathway. Bioengineered. 2021;12(1):8378–8395. DOI:10.1080/21655979.2021.1987092

 PubMed Web of Science ®Google Scholar

Ge X, Liu W, Zhao W, et al. Exosomal TRAnsfer of LCP1 promotes osteosarcoma cell tumorigenesis and metastasis by activating the JAK2/STAT3 Signaling Pathway. Mol Ther Nucleic Acids. 2020;21:900–915.

 PubMedGoogle Scholar

Zhao W, et al. Long non-coding RNA PVT1 encapsulated in bone marrow mesenchymal stem cell-derived exosomes promotes osteosarcoma growth and metastasis by stabilizing ERG and sponging miR-183-5p. Aging (Albany NY). 2019;11(21):9581–9596. DOI:10.18632/aging.102406

 PubMedGoogle Scholar

Qi J, Zhou Y, Jiao Z, et al. Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth through hedgehog signaling pathway. Cell Physiol Biochem. 2017;42(6):2242–2254. DOI:10.1159/000479998

 PubMedGoogle Scholar

Feng D, Li Z, Yang L, et al. BMSC-EV-derived lncRNA NORAD facilitates migration, invasion, and angiogenesis in osteosarcoma cells by regulating CREBBP via Delivery of miR-877-3p. Oxid Med Cell Longev. 2022;2022:8825784.

 PubMed Web of Science ®Google Scholar

Li F, Chen X, Shang C, et al. Bone marrow mesenchymal stem cells-derived extracellular vesicles promote proliferation, invasion and migration of osteosarcoma cells via the lncRNA MALAT1/miR-143/NRSN2/Wnt/β-Catenin Axis. Onco Targets Ther. 2021;14:737–749.

 PubMed Web of Science ®Google Scholar

Shi Z, Wang K, Xing Y, et al. CircNRIP1 encapsulated by bone marrow mesenchymal stem cell–derived extracellular vesicles aggravates osteosarcoma by modulating the miR-532-3p/akt3/pi3k/akt Axis. Front Oncol. 2021;11:658139.

 PubMed Web of Science ®Google Scholar

Wang Y, Chu Y, Li K, et al. Exosomes secreted by adipose-derived mesenchymal stem cells foster metastasis and osteosarcoma proliferation by increasing COLGALT2 Expression. Front Cell Dev Biol. 2020;8:353.

 PubMed Web of Science ®Google Scholar

Zhang K, Dong C, Chen M, et al. Extracellular vesicle-mediated delivery of miR-101 inhibits lung metastasis in osteosarcoma. Theranostics. 2020;10(1):411–425. DOI:10.7150/thno.33482

 PubMed Web of Science ®Google Scholar

Zhang H, Yu Y, Wang J, et al. Macrophages-derived exosomal lncRNA LIFR-AS1 promotes osteosarcoma cell progression via miR-29a/NFIA axis. Cancer Cell Int. 2021;21(1):192. DOI:10.1186/s12935-021-01893-0

 PubMed Web of Science ®Google Scholar

Liu W, Long Q, Zhang W, et al. MiRNA-221-3p derived from M2-polarized tumor-associated macrophage exosomes aggravates the growth and metastasis of osteosarcoma through SOCS3/JAK2/STAT3 axis. Aging (Albany NY. Aging. 2021;13(15):19760–19775. DOI:10.18632/aging.203388

 PubMedGoogle Scholar

Wang L, Wu J, Song S, et al. Plasma exosome-derived sentrin sumo-specific protease 1: a prognostic biomarker in patients with osteosarcoma. Front Oncol. 2021;11:625109.

 PubMedGoogle Scholar

Zhang H, Wang J, Ren T, et al. LncRNA CASC15 is upregulated in osteosarcoma plasma exosomes and CASC15 knockdown inhibits osteosarcoma progression by regulating miR-338-3p/rab14 Axis. onco Targets Ther. 2020;13:12055–12066.

 PubMed Web of Science ®Google Scholar

Li S, Pei Y, Wang W, et al. Extracellular nanovesicles-transmitted circular RNA has_circ_0000190 suppresses osteosarcoma progression. J Cell Mol Med. 2020;24(3):2202–2214. DOI:10.1111/jcmm.14877

 PubMed Web of Science ®Google Scholar

Strzelecka-Kiliszek A, Bozycki L, Mebarek S, et al. Characteristics of minerals in vesicles produced by human osteoblasts hFOB 1.19 and osteosarcoma Saos-2 cells stimulated for mineralization. J Inorg Biochem. 2017;171:100–107.

 PubMed Web of Science ®Google Scholar

Bozycki L, Mroczek J, Bessueille L, et al. Annexins A2, A6 and fetuin-a affect the process of mineralization in vesicles derived from human osteoblastic hfob 1.19 and osteosarcoma saos-2 Cells. Int J Mol Sci. 2021;22(8):3993. DOI:10.3390/ijms22083993

 PubMed Web of Science ®Google Scholar

Yang J, Hu Y, Wang L, et al. Human umbilical vein endothelial cells derived-exosomes promote osteosarcoma cell stemness by activating Notch signaling pathway. Bioengineered. 2021;12(2):11007–11017. DOI:10.1080/21655979.2021.2005220

 PubMed Web of Science ®Google Scholar

Lu Y, Cao G, Lan H, et al. Chondrocyte-derived exosomal miR-195 inhibits osteosarcoma cell proliferation and anti-apoptotic by targeting KIF4A in vitro and in vivo. Transl Oncol. 2022;16:101289.

 PubMed Web of Science ®Google Scholar

Data availability statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study