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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

Effect of CSC-EV stimulation of MSCs on their ability to promote tumor migration and angiogenesisExperiments were performed using 2 week stimulated MSCs. (A) representative light microscopy images of vessel-like structures formed by HUVEC in co-culture for 24 hours with non-stimulated MSCs (left panel) or stimulated MSCs (right panel) (original magnification × 10). (B) quantification of vessel-like structures formed by HUVEC in co-culture with non-stimulated MSCs (white bars) and stimulated MSC (black bars). (C) representative light microscopy images of renal tumor cell migration after 24 hours co-cultured with non-stimulated MSCs (left panel) or stimulated MSCs (right panel) (original magnification × 10). (D) quantification of migration rate of K1 renal tumor cells after 24 hours of co-culture in transwell with non-stimulated MSCs (white bar) or stimulated MSCs (black bar). (E) comparison between CSC-EV fractions (10K, 100K and Total) and EVs derived from proximal tubular epithelial cells (PTEC) and K1 cells stimulated MSCs to induce formation of capillary-like structures. (F) comparison among the capacity of MSCs stimulated by CSC-EV, PTEC-EV or K1-EV fractions to stimulate tumor migration. Each condition is indicated in the abscissa. Statistical analysis was performed by t-test: * indicates statistical difference to the control group (P < 0.05; n = 4).
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Figure 4: Effect of CSC-EV stimulation of MSCs on their ability to promote tumor migration and angiogenesisExperiments were performed using 2 week stimulated MSCs. (A) representative light microscopy images of vessel-like structures formed by HUVEC in co-culture for 24 hours with non-stimulated MSCs (left panel) or stimulated MSCs (right panel) (original magnification × 10). (B) quantification of vessel-like structures formed by HUVEC in co-culture with non-stimulated MSCs (white bars) and stimulated MSC (black bars). (C) representative light microscopy images of renal tumor cell migration after 24 hours co-cultured with non-stimulated MSCs (left panel) or stimulated MSCs (right panel) (original magnification × 10). (D) quantification of migration rate of K1 renal tumor cells after 24 hours of co-culture in transwell with non-stimulated MSCs (white bar) or stimulated MSCs (black bar). (E) comparison between CSC-EV fractions (10K, 100K and Total) and EVs derived from proximal tubular epithelial cells (PTEC) and K1 cells stimulated MSCs to induce formation of capillary-like structures. (F) comparison among the capacity of MSCs stimulated by CSC-EV, PTEC-EV or K1-EV fractions to stimulate tumor migration. Each condition is indicated in the abscissa. Statistical analysis was performed by t-test: * indicates statistical difference to the control group (P < 0.05; n = 4).

Mentions: To evaluate whether MSCs stimulated for 2 weeks with CSC-EVs promoted angiogenesis, MSCs were plated in the upper transwell chamber and human umbilical vein endothelial cells (HUVEC) in the lower. As shown in Fig. 4A and 4B, CSC-EV-stimulated MSCs significantly increased the in vitro vessel-like formation by HUVEC (HUVEC + MSC STI).


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)

Effect of CSC-EV stimulation of MSCs on their ability to promote tumor migration and angiogenesisExperiments were performed using 2 week stimulated MSCs. (A) representative light microscopy images of vessel-like structures formed by HUVEC in co-culture for 24 hours with non-stimulated MSCs (left panel) or stimulated MSCs (right panel) (original magnification × 10). (B) quantification of vessel-like structures formed by HUVEC in co-culture with non-stimulated MSCs (white bars) and stimulated MSC (black bars). (C) representative light microscopy images of renal tumor cell migration after 24 hours co-cultured with non-stimulated MSCs (left panel) or stimulated MSCs (right panel) (original magnification × 10). (D) quantification of migration rate of K1 renal tumor cells after 24 hours of co-culture in transwell with non-stimulated MSCs (white bar) or stimulated MSCs (black bar). (E) comparison between CSC-EV fractions (10K, 100K and Total) and EVs derived from proximal tubular epithelial cells (PTEC) and K1 cells stimulated MSCs to induce formation of capillary-like structures. (F) comparison among the capacity of MSCs stimulated by CSC-EV, PTEC-EV or K1-EV fractions to stimulate tumor migration. Each condition is indicated in the abscissa. Statistical analysis was performed by t-test: * indicates statistical difference to the control group (P < 0.05; n = 4).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Effect of CSC-EV stimulation of MSCs on their ability to promote tumor migration and angiogenesisExperiments were performed using 2 week stimulated MSCs. (A) representative light microscopy images of vessel-like structures formed by HUVEC in co-culture for 24 hours with non-stimulated MSCs (left panel) or stimulated MSCs (right panel) (original magnification × 10). (B) quantification of vessel-like structures formed by HUVEC in co-culture with non-stimulated MSCs (white bars) and stimulated MSC (black bars). (C) representative light microscopy images of renal tumor cell migration after 24 hours co-cultured with non-stimulated MSCs (left panel) or stimulated MSCs (right panel) (original magnification × 10). (D) quantification of migration rate of K1 renal tumor cells after 24 hours of co-culture in transwell with non-stimulated MSCs (white bar) or stimulated MSCs (black bar). (E) comparison between CSC-EV fractions (10K, 100K and Total) and EVs derived from proximal tubular epithelial cells (PTEC) and K1 cells stimulated MSCs to induce formation of capillary-like structures. (F) comparison among the capacity of MSCs stimulated by CSC-EV, PTEC-EV or K1-EV fractions to stimulate tumor migration. Each condition is indicated in the abscissa. Statistical analysis was performed by t-test: * indicates statistical difference to the control group (P < 0.05; n = 4).
Mentions: To evaluate whether MSCs stimulated for 2 weeks with CSC-EVs promoted angiogenesis, MSCs were plated in the upper transwell chamber and human umbilical vein endothelial cells (HUVEC) in the lower. As shown in Fig. 4A and 4B, CSC-EV-stimulated MSCs significantly increased the in vitro vessel-like formation by HUVEC (HUVEC + MSC STI).

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