Natural killer cells acquire CD73 expression upon exposure to mesenchymal stem cells

Chatterjee, Debanjana; Tufa, Dejene M.; Baehre, Heike; Hass, Ralf; Schmidt, Reinhold; Jacobs, Roland

doi:10.1182/blood-2013-09-524827

Cited by 57 publications

(46 citation statements)

References 8 publications

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“…According to functional changes by mRNA and/or protein transfer or protein induction via specific communication processes, a previous work confirmed that cellular interactions can promote an MSC-mediated protein expression in MDA-MB-231 breast cancer or natural killer cells, which partially involves GJIC and notch signaling [26,56]. Furthermore, this study demonstrated that the direct interactions include the transfer and exchange of cellular material.…”

Section: Discussionmentioning

confidence: 72%

Human Mesenchymal Stroma/Stem Cells Exchange Membrane Proteins and Alter Functionality During Interaction with Different Tumor Cell Lines

Yang

Otte

Hass

2015

Stem Cells and Development

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To analyze effects of cellular interaction between human mesenchymal stroma/stem cells (MSC) and different cancer cells, direct co-cultures were performed and revealed significant growth stimulation of the tumor populations and a variety of protein exchanges. More than 90% of MCF-7 and primary human HBCEC699 breast cancer cells as well as NIH:OVCAR-3 ovarian adenocarcinoma cells acquired CD90 proteins during MSC co-culture, respectively. Furthermore, SK-OV-3 ovarian cancer cells progressively elevated CD105 and CD90 proteins in co-culture with MSC. Primary small cell hypercalcemic ovarian carcinoma cells (SCCOHT-1) demonstrated undetectable levels of CD73 and CD105; however, both proteins were significantly increased in the presence of MSC. This co-culture-mediated protein induction was also observed at transcriptional levels and changed functionality of SCCOHT-1 cells by an acquired capability to metabolize 5¢cAMP. Moreover, exchange between tumor cells and MSC worked bidirectional, as undetectable expression of epithelial cell adhesion molecule (EpCAM) in MSC significantly increased after co-culture with SK-OV-3 or NIH:OVCAR-3 cells. In addition, a small population of chimeric/hybrid cells appeared in each MSC/tumor cell co-culture by spontaneous cell fusion. Immune fluorescence demonstrated nanotube structures and exosomes between MSC and tumor cells, whereas cytochalasin-D partially abolished the intercellular protein transfer. More detailed functional analysis of FACS-separated MSC and NIH:OVCAR-3 cells after co-culture revealed the acquisition of epithelial cell-specific properties by MSC, including increased gene expression for cytokeratins and epithelial-like differentiation factors. Vice versa, a variety of transcriptional regulatory genes were downmodulated in NIH:OVCAR-3 cells after co-culture with MSC. Together, these mutual cellular interactions contributed to functional alterations in MSC and tumor cells.

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Section: Discussionmentioning

confidence: 72%

Human Mesenchymal Stroma/Stem Cells Exchange Membrane Proteins and Alter Functionality During Interaction with Different Tumor Cell Lines

Yang

Otte

Hass

2015

Stem Cells and Development

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“…Through the increasing adenosine, CD73 contribute to immunosuppressive effects of anti-tumor T cells [48] and regulate adaptive responses upon hypoxia[49]. Furthermore, CD73 expression in tumor cells and tumor environment are required for tumor angiogenesis [50].The percentage of CD73+ Natural killer (NK) NK cells increases significantly on coculture with MSCs and thus acquires the ability to convert AMP into adenosine [51]. Epithelial mesenchymal transition (EMT) is a fundamental biologic process during which epithelial cells lose their polarity and change to a mesenchymal phenotype [52], [53], [54].…”

Section: Discussionmentioning

confidence: 99%

CD117 Expression in Fibroblasts-Like Stromal Cells Indicates Unfavorable Clinical Outcomes in Ovarian Carcinoma Patients

Huang

Yuan

et al. 2014

PLoS ONE

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The stem cell factor (SCF) receptor CD117 (c-kit), is widely used for identification of hematopoietic stem cells and cancer stem cells. Moreover, CD117 expression in carcinoma cells indicates a poor prognosis in a variety of cancers. However the potential expression in tumor microenvironment and the biological and clinical impact are currently not reported. The expression of CD117 was immunohistochemically evaluated in a serial of 242 epithelial ovarian cancer (EOC) cases. Thirty-eight out of 242 cases were CD117 positive in fibroblast-like stromal cells and 22 cases were positive in EOC cells. Four cases were both positive in fibroblast-like stromal cells and EOC cells for CD117. CD117 expression in fibroblast-like stromal cells in ovarian carcinoma was closely linked to advanced FIGO stage, poor differentiation grade and histological subtype (p<0.05), and it was significantly associated with poor overall survival (OS) and progression free survival (PFS) (Kaplan-Meier analysis; p<0.05, log-rank test). CD117 expression in ovarian carcinoma cells was not associated with these clinicopathological variables. The CD117 positive fibroblast-like stromal cells were all positive for mesenchymal stem/stromal cell (MSC) marker CD73 but negative for fibroblast markers fibroblast activation protein (FAP) and α smooth muscle actin (α-SMA), indicating that the CD117+/CD73+ fibroblast-like stromal cells are a subtype of mesenchymal stem cells in tumor stroma, although further characterization of these cells are needed. It is concluded herewith that the presence of CD117+/CD73+ fibroblast-like stromal cells in ovarian carcinoma is an unfavorable clinical outcome indication.

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“…These results were not surprising, because we have demonstrated that ADO can be produced by CD16 2 CD56 bright NK cells using either the canonical or the alternative pathway. Moreover, b-g-meATP may also activate NK cells, either by interacting with P 2 X receptor instead of inhibiting CD203a/PC-1 enzymatic activity (29), or inducing cAMP formation. Surprisingly a-b-meADP, a specific inhibitor of CD73, did not restore T cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

CD56brightCD16− NK Cells Produce Adenosine through a CD38-Mediated Pathway and Act as Regulatory Cells Inhibiting Autologous CD4+ T Cell Proliferation

Morandi

Horenstein

Chillemi

et al. 2015

The Journal of Immunology

119

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Recent studies suggested that human CD56brightCD16− NK cells may play a role in the regulation of the immune response. Since the mechanism(s) involved have not yet been elucidated, in the present study we have investigated the role of nucleotide-metabolizing enzymes that regulate the extracellular balance of nucleotides/nucleosides and produce the immunosuppressive molecule adenosine (ADO). Peripheral blood CD56dimCD16+ and CD56brightCD16− NK cells expressed similar levels of CD38. CD39, CD73, and CD157 expression was higher in CD56brightCD16− than in CD56dimCD16+ NK cells. CD57 was mostly expressed by CD56dimCD16+ NK cells. CD203a/PC-1 expression was restricted to CD56brightCD16− NK cells. CD56brightCD16− NK cells produce ADO and inhibit autologous CD4+ T cell proliferation. Such inhibition was 1) reverted pretreating CD56brightCD16− NK cells with a CD38 inhibitor and 2) increased pretreating CD56brightCD16− NK cells with a nucleoside transporter inhibitor, which increase extracellular ADO concentration. CD56brightCD16− NK cells isolated from the synovial fluid of juvenile idiopathic arthritis patients failed to inhibit autologous CD4+ T cell proliferation. Such functional impairment could be related to 1) the observed reduced CD38/CD73 expression, 2) a peculiar ADO production kinetics, and 3) a different expression of ADO receptors. In contrast, CD56brightCD16− NK cells isolated from inflammatory pleural effusions display a potent regulatory activity. In conclusion, CD56brightCD16− NK cells act as “regulatory cells” through ADO produced by an ectoenzymes network, with a pivotal role of CD38. This function may be relevant for the modulation of the immune response in physiological and pathological conditions, and it could be impaired during autoimmune/inflammatory diseases.

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Natural killer cells acquire CD73 expression upon exposure to mesenchymal stem cells

Cited by 57 publications

References 8 publications

Human Mesenchymal Stroma/Stem Cells Exchange Membrane Proteins and Alter Functionality During Interaction with Different Tumor Cell Lines

Human Mesenchymal Stroma/Stem Cells Exchange Membrane Proteins and Alter Functionality During Interaction with Different Tumor Cell Lines

CD117 Expression in Fibroblasts-Like Stromal Cells Indicates Unfavorable Clinical Outcomes in Ovarian Carcinoma Patients

CD56brightCD16− NK Cells Produce Adenosine through a CD38-Mediated Pathway and Act as Regulatory Cells Inhibiting Autologous CD4+ T Cell Proliferation

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