Human umbilical cord mesenchymal stem cell-derived extracellular vesicles promote lung adenocarcinoma growth by transferring miR-410

Abstract

Although accumulating evidence has linked mesenchymal stem cells (MSCs) with tumor growth, the underlying mechanisms are poorly understood. Here, we demonstrated for the first time that human umbilical cord MSCs (hUCMSCs) dramatically increased the growth of lung adenocarcinoma (LUAD) cancer cells in a xenograft tumor model. Then, we observed that hUCMSC-derived extracellular vesicles (hUCMSC-EVs) contribute to the hUCMSC-promoted LUAD cell growth through a direct effect on LUAD cells. Furthermore, we showed that hUCMSC-EV-mediated LUAD growth is associated with increased proliferation and decreased apoptosis in LUAD cells, concomitant with reduced PTEN expression mediated by the hUCMSC-EV-transmitted miR-410. Our findings provide novel insights into the intercellular communications between cancer cells and MSCs through MSC-EV-miRNA and suggest that modification of hUCMSC-EVs might be an attractive therapeutic option for the clinical application of hUCMSC-EVs that would reduce unwanted side effects.

Extracellular vesicles from human umbilical cord mesenchymal stem cells improve nerve regeneration after sciatic nerve transection in rats

“…We successfully extracted hUCMSC‐EVs, which presented a cup‐shaped membrane structure when viewed through TEM. The sizes and shapes of the hUCMSC‐EVs that we obtained in the present study are consistent those of hUCMSC‐EVs that we collected in a previous work …”

“…These tests revealed that hUCMSCs have osteogenic and adipogenic differentiation potential. 17 Phycoerythrin (PE)-conjugated CD14, CD19, CD34, CD45, CD73…”

“…A transmission electron microscope (TEM) was used to identify the morphology of hUCMSC-EVs as previously described. 17 Filtered EVs were resuspended in PBS, incubated and stained with 20 μL of the directly fluorescent antibody CD63 (BD Biosciences) for the detection of the typical surface markers of hUCMSC-EVs.…”

Mesenchymal Stem Cells Beyond Regenerative Medicine

“…These MSC properties of cancer support are originally licensed by tumorinfiltrating macrophages which establish a pro-inflammatory chemotactants-studded milieu (Coffelt et al, 2009;Rigo et al, 2010). This milieu evokes MSCs to (i) differentiate into highly proliferative myofibroblasts (Von Ahrens et al, 2017) and vascular cells , (ii) produce tumor-nurturing pro-angiogenic cytokines, miRNA, and exosomes (Roccaro et al, 2013;Zhang et al, 2013;Dong et al, 2018), (iii) secrete extracellular matrix-forming lysosomal oxidase (El-Haibi et al, 2012), (iv) provide a niche for malignant cells to thrive (Lin et al, 2019), and (v) adopt the immunomodulatory MSC2 phenotype (see section "Immunological Properties: A Paradigm") (Patel et al, 2010). As previously mentioned, MSC2 further polarizes macrophages into the M2 phenotype which is pro-tumorigenic (Rivera-Cruz et al, 2017).…”

Role of microRNA‐410 in molecular oncology: A double edged sword

“…Interestingly, the levels of miR‐410 were notably enhanced in lung adenocarcinoma cells after incubation with hUCMSC‐EVs. Phosphatase and tensin homolog (PTEN) was found to be directly regulated by miR‐410 as evidenced by reduced PTEN levels in the tumors of hUCMSC‐EV‐pre‐treated mice …”