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Extracellular vesicles derived from renal cancer stem cells induce a pro-tumorigenic phenotype in mesenchymal stromal cells.

Lindoso RS, Collino F, Camussi G - Oncotarget (2015)

Bottom Line: We found that CSC-derived EVs promoted persistent phenotypical changes in MSCs characterized by an increased expression of genes associated with cell migration (CXCR4, CXCR7), matrix remodeling (COL4A3), angiogenesis and tumor growth (IL-8, Osteopontin and Myeloperoxidase).Moreover, EV-stimulated MSCs enhanced migration of renal tumor cells and induced vessel-like formation.In conclusion, CSC-derived EVs induced phenotypical changes in MSCs that are associated with tumor growth.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Sciences and Molecular Biotechnology Center University of Torino, Torino, Italy.

ABSTRACT
Renal carcinomas have been shown to contain a population of cancer stem cells (CSCs) that present self-renewing capacity and support tumor growth and metastasis. CSCs were shown to secrete large amount of extracellular vesicles (EVs) that can transfer several molecules (proteins, lipids and nucleic acids) and induce epigenetic changes in target cells. Mesenchymal Stromal Cells (MSCs) are susceptible to tumor signalling and can be recruited to tumor regions. The precise role of MSCs in tumor development is still under debate since both pro- and anti-tumorigenic effects have been reported. In this study we analysed the participation of renal CSC-derived EVs in the interaction between tumor and MSCs. We found that CSC-derived EVs promoted persistent phenotypical changes in MSCs characterized by an increased expression of genes associated with cell migration (CXCR4, CXCR7), matrix remodeling (COL4A3), angiogenesis and tumor growth (IL-8, Osteopontin and Myeloperoxidase). EV-stimulated MSCs exhibited in vitro an enhancement of migration toward the tumor conditioned medium. Moreover, EV-stimulated MSCs enhanced migration of renal tumor cells and induced vessel-like formation. In vivo, EV-stimulated MSCs supported tumor development and vascularization, when co-injected with renal tumor cells. In conclusion, CSC-derived EVs induced phenotypical changes in MSCs that are associated with tumor growth.

No MeSH data available.


Related in: MedlinePlus

MSC migration after CSC-EV stimulation(A) chemoattraction potential of CSC-EVs was assessed by evaluation of migration of normal MSCs through transwell porous membrane in the presence (black bar) or absence (white bar) of these EVs in the lower compartment of the transwell. (B) migration of MSCs after 72 hours stimulation with CSC-EVs (black bars) was evaluated by placing in the lower compartment of transwell, the tumor conditioned medium depleted of EVs or DMEM alone. Non-stimulated MSCs were used as control (white bars). (C) migration of MSCs after 2 week stimulus (black bars) versus tumor conditioned medium depleted of EVs or DMEM alone. Non-stimulated MSCs were used as control (white bars). Migration was assessed after 24 hours incubation. Statistical analysis was performed by ANOVA with Newman-Keuls multicomparison test: * indicates statistical difference to the control group maintained in the same experimental condition (P < 0.05; n = 5).
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Figure 2: MSC migration after CSC-EV stimulation(A) chemoattraction potential of CSC-EVs was assessed by evaluation of migration of normal MSCs through transwell porous membrane in the presence (black bar) or absence (white bar) of these EVs in the lower compartment of the transwell. (B) migration of MSCs after 72 hours stimulation with CSC-EVs (black bars) was evaluated by placing in the lower compartment of transwell, the tumor conditioned medium depleted of EVs or DMEM alone. Non-stimulated MSCs were used as control (white bars). (C) migration of MSCs after 2 week stimulus (black bars) versus tumor conditioned medium depleted of EVs or DMEM alone. Non-stimulated MSCs were used as control (white bars). Migration was assessed after 24 hours incubation. Statistical analysis was performed by ANOVA with Newman-Keuls multicomparison test: * indicates statistical difference to the control group maintained in the same experimental condition (P < 0.05; n = 5).

Mentions: When unstimulated MSCs were plated in the upper chamber of transwell, no direct chemoattraction was observed by CSC-EVs (EVs) (Fig. 2A) or CSC conditioned medium (CTR TUM MED) (Fig. 2B, 2C) present in the lower chamber. When MSCs were pre-stimulated with CSC-EVs for a short time (72 h) and then challenged with CSC conditioned medium, a slight but not significant increase in migration was observed (STI TUM MED) (Fig. 2B). In contrast, when MSCs were pre-stimulated for 2 weeks with CSC-EVs, a significant increase in MSC chemo-attraction towards CSC conditioned medium was observed (STI TUM MED) (Fig. 2C).


Extracellular vesicles derived from renal cancer stem cells induce a pro-tumorigenic phenotype in mesenchymal stromal cells.

Lindoso RS, Collino F, Camussi G - Oncotarget (2015)

MSC migration after CSC-EV stimulation(A) chemoattraction potential of CSC-EVs was assessed by evaluation of migration of normal MSCs through transwell porous membrane in the presence (black bar) or absence (white bar) of these EVs in the lower compartment of the transwell. (B) migration of MSCs after 72 hours stimulation with CSC-EVs (black bars) was evaluated by placing in the lower compartment of transwell, the tumor conditioned medium depleted of EVs or DMEM alone. Non-stimulated MSCs were used as control (white bars). (C) migration of MSCs after 2 week stimulus (black bars) versus tumor conditioned medium depleted of EVs or DMEM alone. Non-stimulated MSCs were used as control (white bars). Migration was assessed after 24 hours incubation. Statistical analysis was performed by ANOVA with Newman-Keuls multicomparison test: * indicates statistical difference to the control group maintained in the same experimental condition (P < 0.05; n = 5).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480728&req=5

Figure 2: MSC migration after CSC-EV stimulation(A) chemoattraction potential of CSC-EVs was assessed by evaluation of migration of normal MSCs through transwell porous membrane in the presence (black bar) or absence (white bar) of these EVs in the lower compartment of the transwell. (B) migration of MSCs after 72 hours stimulation with CSC-EVs (black bars) was evaluated by placing in the lower compartment of transwell, the tumor conditioned medium depleted of EVs or DMEM alone. Non-stimulated MSCs were used as control (white bars). (C) migration of MSCs after 2 week stimulus (black bars) versus tumor conditioned medium depleted of EVs or DMEM alone. Non-stimulated MSCs were used as control (white bars). Migration was assessed after 24 hours incubation. Statistical analysis was performed by ANOVA with Newman-Keuls multicomparison test: * indicates statistical difference to the control group maintained in the same experimental condition (P < 0.05; n = 5).
Mentions: When unstimulated MSCs were plated in the upper chamber of transwell, no direct chemoattraction was observed by CSC-EVs (EVs) (Fig. 2A) or CSC conditioned medium (CTR TUM MED) (Fig. 2B, 2C) present in the lower chamber. When MSCs were pre-stimulated with CSC-EVs for a short time (72 h) and then challenged with CSC conditioned medium, a slight but not significant increase in migration was observed (STI TUM MED) (Fig. 2B). In contrast, when MSCs were pre-stimulated for 2 weeks with CSC-EVs, a significant increase in MSC chemo-attraction towards CSC conditioned medium was observed (STI TUM MED) (Fig. 2C).

Bottom Line: We found that CSC-derived EVs promoted persistent phenotypical changes in MSCs characterized by an increased expression of genes associated with cell migration (CXCR4, CXCR7), matrix remodeling (COL4A3), angiogenesis and tumor growth (IL-8, Osteopontin and Myeloperoxidase).Moreover, EV-stimulated MSCs enhanced migration of renal tumor cells and induced vessel-like formation.In conclusion, CSC-derived EVs induced phenotypical changes in MSCs that are associated with tumor growth.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Sciences and Molecular Biotechnology Center University of Torino, Torino, Italy.

ABSTRACT
Renal carcinomas have been shown to contain a population of cancer stem cells (CSCs) that present self-renewing capacity and support tumor growth and metastasis. CSCs were shown to secrete large amount of extracellular vesicles (EVs) that can transfer several molecules (proteins, lipids and nucleic acids) and induce epigenetic changes in target cells. Mesenchymal Stromal Cells (MSCs) are susceptible to tumor signalling and can be recruited to tumor regions. The precise role of MSCs in tumor development is still under debate since both pro- and anti-tumorigenic effects have been reported. In this study we analysed the participation of renal CSC-derived EVs in the interaction between tumor and MSCs. We found that CSC-derived EVs promoted persistent phenotypical changes in MSCs characterized by an increased expression of genes associated with cell migration (CXCR4, CXCR7), matrix remodeling (COL4A3), angiogenesis and tumor growth (IL-8, Osteopontin and Myeloperoxidase). EV-stimulated MSCs exhibited in vitro an enhancement of migration toward the tumor conditioned medium. Moreover, EV-stimulated MSCs enhanced migration of renal tumor cells and induced vessel-like formation. In vivo, EV-stimulated MSCs supported tumor development and vascularization, when co-injected with renal tumor cells. In conclusion, CSC-derived EVs induced phenotypical changes in MSCs that are associated with tumor growth.

No MeSH data available.


Related in: MedlinePlus