Tumor Mesenchymal Stem‐Like Cell as a Prognostic Marker in Primary Glioblastoma

Yoon, Seon‐Jin; Shim, Jae Yong; Chang, Jong Hee; Moon, Ju Hyung; Roh, Tae Hoon; Sung, Kyu Bo; Lee, Ji Hyun; Kim, Eui Hyun; Kim, Sun Ho; Hong, Yong Kil; Lee, Su Jae; Huh, Yong Min; Kang, Seok‐Gu

doi:10.1155/2016/6756983

Cited by 19 publications

(24 citation statements)

References 43 publications

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“…Other studies isolated MSC-like cells from GB and these cells were shown to increase angiogenesis, and GB cell proliferation and invasion [ 54 – 58 ]. Consistent with these findings, it has been recently observed that the percentage of GB-associated MSC-like cells is inversely correlated with overall survival, indicating a role for these cells in promoting the aggressive behavior of GB [ 59 , 60 ]. All these data raise the question if MSCs are interesting candidates as cellular vehicles for the delivery of a therapeutic molecule in a GB context.…”

Section: Discussionsupporting

confidence: 70%

Human mesenchymal stromal cells as cellular drug-delivery vectors for glioblastoma therapy: a good deal?

Clavreul

Pourbaghi-Masouleh

Roger

et al. 2017

J Exp Clin Cancer Res

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BackgroundGlioblastoma (GB) is the most malignant brain tumor in adults. It is characterized by angiogenesis and a high proliferative and invasive capacity. Standard therapy (surgery, radiotherapy and chemotherapy with temozolomide) is of limited efficacy. Innovative anticancer drugs targeting both tumor cells and angiogenesis are urgently required, together with effective systems for their delivery to the brain. We assessed the ability of human mesenchymal stromal cells (MSCs) to uptake the multikinase inhibitor, sorafenib (SFN), and to carry this drug to a brain tumor following intranasal administration.MethodMSCs were primed with SFN and drug content and release were quantified by analytical chemistry techniques. The ability of SFN-primed MSCs to inhibit the survival of the human U87MG GB cell line and endothelial cells was assessed in in vitro assays. These cells were then administered intranasally to nude mice bearing intracerebral U87MG xenografts. Their effect on tumor growth and angiogenesis was evaluated by magnetic resonance imaging and immunofluorescence analyses, and was compared with the intranasal administration of unprimed MSCs or SFN alone.ResultsMSCs took up about 9 pg SFN per cell, with no effect on viability, and were able to release 60% of the primed drug. The cytostatic activity of the released SFN was entirely conserved, resulting in a significant inhibition of U87MG and endothelial cell survival in vitro. Two intranasal administrations of SFN-primed MSCs in U87MG-bearing mice resulted in lower levels of tumor angiogenesis than the injection of unprimed MSCs or SFN alone, but had no effect on tumor volume. We also observed an increase in the proportion of small intratumoral vessels in animals treated with unprimed MSCs; this effect being abolished if the MSCs were primed with SFN.ConclusionWe show the potential of MSCs to carry SFN to brain tumors following an intranasal administration. However, the therapeutic effect is modest probably due to the pro-tumorigenic properties of MSCs, which may limit the action of the released SFN. This calls into question the suitability of MSCs for use in GB therapy and renders it necessary to find methods guaranteeing the safety of this cellular vector after drug delivery.

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Section: Discussionsupporting

confidence: 70%

Human mesenchymal stromal cells as cellular drug-delivery vectors for glioblastoma therapy: a good deal?

Clavreul

Pourbaghi-Masouleh

Roger

et al. 2017

J Exp Clin Cancer Res

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“…In line with this trend, tMSLCs are recently defined as stromal cells interacting with GBM cells and their potential role in tumor progression has received intensive attention [11, 12, 23–25]. …”

Section: Discussionmentioning

confidence: 99%

Tumor-associated mesenchymal stem-like cells provide extracellular signaling cue for invasiveness of glioblastoma cells

et al. 2016

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Hyaluronic acid (HA) is abundant in tumor microenvironment and closely associated with invasiveness of glioblastoma (GBM) cells. However, the cellular mechanism underlying HA-rich microenvironment in GBM remains unexplored. Here, we show that tumor-associated mesenchymal stem-like cells (tMSLCs) contribute to abundance of hyaluronic acid (HA) in tumor microenvironment through HA synthase-2 (HAS2) induction, and thereby enhances invasiveness of GBM cells. In an autocrine manner, C5a secreted by tMSLCs activated ERK MAPK for HAS2 induction in tMSLCs. Importantly, HA acted as a signaling ligand of its cognate receptor RHAMM for intracellular signaling activation underlying invasiveness of GBM cells. Taken together, our study suggests that tMSLCs contribute to HA-rich proinvasive ECM microenvironment in GBM.

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“…Recently, tMSLCs have been reported as stromal cells interacting with GBM cells, and their potential role in tumor progression has received intensive attention ( 27 , 28 ). However, it remains controversial whether tMSLCs in the tumor microenvironment play a role in cancer promotion or suppression ( 29 – 33 ).…”

Section: Discussionmentioning

confidence: 99%

“…These contrasting results could be caused by differences in their origin and/or the type of tumor. Thus, we previously isolated tMSLCs directly from human GBM surgical specimens and found that their presence is closely correlated with the prognosis of patients ( 28 ). In this current study, we provide another strong evidence that tMSLCs act as stromal cells promoting GBM progression by force-mediated proinvasive ECM remodeling.…”

Section: Discussionmentioning

confidence: 99%

Force-mediated proinvasive matrix remodeling driven by tumor-associated mesenchymal stem-like cells in glioblastoma

et al. 2018

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In carcinoma, cancer-associated fibroblasts participate in force-mediated extracellular matrix (ECM) remodeling, consequently leading to invasion of cancer cells. Likewise, the ECM remodeling actively occurs in glioblastoma (GBM) and the consequent microenvironmental stiffness is strongly linked to migration behavior of GBM cells. However, in GBM the stromal cells responsible for force-mediated ECM remodeling remain unidentified. We show that tumor-associated mesenchymal stem-like cells (tMSLCs) provide a proinvasive matrix condition in GBM by force-mediated ECM remodeling. Importantly, CCL2-mediated Janus kinase 1 (JAK1) activation increased phosphorylation of myosin light chain 2 in tMSLCs and led to collagen assembly and actomyosin contractility. Collectively, our findings implicate tMSLCs as stromal cells providing force-mediated proinvasive ECM remodeling in the GBM microenvironment, and reminiscent of fibroblasts in carcinoma.

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Tumor Mesenchymal Stem‐Like Cell as a Prognostic Marker in Primary Glioblastoma

Cited by 19 publications

References 43 publications

Human mesenchymal stromal cells as cellular drug-delivery vectors for glioblastoma therapy: a good deal?

Human mesenchymal stromal cells as cellular drug-delivery vectors for glioblastoma therapy: a good deal?

Tumor-associated mesenchymal stem-like cells provide extracellular signaling cue for invasiveness of glioblastoma cells

Force-mediated proinvasive matrix remodeling driven by tumor-associated mesenchymal stem-like cells in glioblastoma

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