Induction of apoptosis in glioma cells requires cell-to-cell contact with human umbilical cord blood stem cells

Abstract

Abstract. We have previously demonstrated the multipotent nature of human umbilical cord blood stem cells (hUCB). In this study, we have attempted to show the use of hUCB in glioma therapy. We used hUCB enriched in CD44 and CD133 cells for our studies and observed that glioma cells co-cultured with hUCB undergo apoptosis. To prove the role of cell-tocell contact in the induction of apoptotic events, we used a modified 0.22 μm Boyden's chamber where the upper surface was used to culture glioma cells (SNB19 or U87) or xenografts (4910 or 5310) and the lower surface to culture hUCB. TUNEL assay was carried out to determine the degree of apoptotic induction and we observed that glioma or xenograft cells cocultured with hUCB had a higher number of TUNEL-positive characteristics (63±6%) compared to the controls. Further, we co-cultured glioma cells labeled with lipophilic green fluorescent dye and hUCB labeled with lipophilic red fluorescent dye. FACS analysis of cells collected from the upper and lower surfaces revealed that glioma cells had taken up red fluorescent dye from the stem cells (70±3%) when compared to glioma cells co-cultured with fibroblast cells (15±4%). The apoptotic events in the glioma and xenograft cells co-cultured with hUCB were also confirmed by Western blot analysis for the cleavage of PARP and activation of caspase 8. In addition, elevated levels of CHK-2 levels and downregulation of MAP2K1 were observed in glioma cells co-cultured with hUCB indicating the DNA damage and decrease in cell survival. Nude mice, intracranially implanted with luciferase-expressing U87 cells followed by implantation of hUCB or human fibroblast cells showed retardation of intracranial tumors in hUCB-implanted mice. Taken together, these results demonstrate that hUCB have therapeutic potential with possible clinical implications.

RETRACTED ARTICLE: Umbilical cord tissue-derived mesenchymal stem cells induce apoptosis in PC-3 prostate cancer cells through activation of JNK and downregulation of PI3K/AKT signaling

“…MSCs are usually isolated from umbilical cord blood or tissues and adipocytes [ 34 - 36 ]. Although much evidence suggests that MSCs can be applied to several diseases, such as cancers [ 1 , 22 , 24 ], cardiac disease [ 8 , 37 ], stroke [ 6 ], and Parkinson and Huntington diseases [ 3 ], the underlying antitumor mechanism of MSCs was not fully understood until now. Thus, in the current study, the antitumor signaling of hUCMSCs was elucidated in PC-3 prostate cancer cells.…”

“…Also, hUCMSCs have an immune-suppressive effect or reduced immunogenicity [ 20 ] and express vascular endothelial growth factor (VEGF) and interleukin (IL)-6 [ 18 , 21 ]. Recently, UCB-derived MSCs showed cytotoxicity against glioma [ 22 ] and Kaposi sarcoma [ 23 ], and umbilical cord mesenchymal stem cells suppressed the growth of breast cancer cells [ 24 - 26 ]. Based on previous evidence, in the present study, we investigated the antitumor mechanism of hUCMSCs in PC-3 prostate cancer cells and report that hUCMSCs induce antiproliferative and apoptotic effects in PC-3 cells via activation of JNK and inhibition of the PI3K/AKT pathway in either direct or indirect culture conditions.…”

Regulation of Glioblastoma Progression by Cord Blood Stem Cells Is Mediated by Downregulation of Cyclin D1

“…Previously we have shown that hUCBSC plays an important role in inducing apoptosis [25] , [26] and reduced migration [27] in glioblastoma cell lines. We focused our present study to determine the regulation of cell cycle progression in the glioma cells when co-cultured with hUCBSC and attempted to determine the potential of hUCBSC to mediate down regulation of cyclin D1, thereby reducing the cell cycle progression by arresting them at G 0 -G 1 phase.…”

“…Further, cyclin D1 was co-localized with CD81, confirming the presence of hUCBSC in treated brain samples. In both the cases, during co-localization of hUCBSC with glioma cells, it has been shown that hUCBSC should be in contact with the glioma cells to show their effect [24] , [25] . It is plausible that hUCBSC reduced cyclin D1 expression in glioma cells within their contact and in the surrounding areas ( Figs.…”

The role of stem cells in tumor targeting and growth suppression of gliomas

“…Cytokines, such as vascular endothelial cell growth factors (VEGFs), tumor growth factors (TGFs), epidermal growth factors (EGFs), platelet-derived growth factors (PDGF), monocyte chemoattractant protein-1 (MCP-1), and interleukin-8 (IL-8), which are released from the neoplasm or inflammatory tissues, are all possible candidates for tropism of stem cells. 34 – 36 Mesenchymal cells augment VEGF-induced angiogenesis in vitro. 37 It is recognized that the factors released from cancer cells promote the movement of endothelial cell progenitors and stromal cell progenitors from the bone marrow toward the tumor 38 , 39 or tissues surrounding the tumor, which enhances the formation of tumor-stroma.…”