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Endothelial cells promote stem-like phenotype of glioma cells through activating the Hedgehog pathway.

Yan GN, Yang L, Lv YF, Shi Y, Shen LL, Yao XH, Guo QN, Zhang P, Cui YH, Zhang X, Bian XW, Guo DY - J. Pathol. (2014)

Bottom Line: Microenvironmental regulation of cancer stem cells (CSCs) strongly influences the onset and spread of cancer.We observed that CD133(+) GSCs were located closely to Shh(+) endothelial cells in specimens of human glioblastoma multiforme (GBM).Knockdown of Smo in glioma cells led to a significant reduction of their CSC-like phenotype formation in vitro and in vivo.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University and Key Laboratory of Tumour Immunopathology, Ministry of Education of China, Chongqing, 400038, People's Republic of China.

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Inhibition of Hedgehog pathway hampers the appearance of GSC-like phenotype of glioma cells. As compared to mock-GL261 alone or mock-GL261 cells co-cultured with b.END3, shSmo–GL261 alone or shSmo–GL261 cells co-cultured with b.END3 cells formed smaller tumour spheres (A; scale bar = 100 µm) and fewer tumour spheres (B; *p < 0.05), respectively. CD133 expression of shSmo–GL261 cells was reduced (C) and expressions of Sox2, Olig2 and Bmi1 were significantly reduced (D), respectively, tubulin was used as control. Subcutaneous allografts generated by shSmo–GL261 cells, with or without b.END3 cells, were significantly smaller in volume as compared to mock GL261 cells with or without b.END3 cells (E; *p < 0.05), respectively; −, wild-type GL261 cells; +, Smo-knockdown GL261 cells.
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fig05: Inhibition of Hedgehog pathway hampers the appearance of GSC-like phenotype of glioma cells. As compared to mock-GL261 alone or mock-GL261 cells co-cultured with b.END3, shSmo–GL261 alone or shSmo–GL261 cells co-cultured with b.END3 cells formed smaller tumour spheres (A; scale bar = 100 µm) and fewer tumour spheres (B; *p < 0.05), respectively. CD133 expression of shSmo–GL261 cells was reduced (C) and expressions of Sox2, Olig2 and Bmi1 were significantly reduced (D), respectively, tubulin was used as control. Subcutaneous allografts generated by shSmo–GL261 cells, with or without b.END3 cells, were significantly smaller in volume as compared to mock GL261 cells with or without b.END3 cells (E; *p < 0.05), respectively; −, wild-type GL261 cells; +, Smo-knockdown GL261 cells.

Mentions: To determine whether HH pathway activation mediated the promotion of a GSC-like phenotype, we generated Smo-knockdown GL261 cells (shSmo–GL261; see supplementary material, Figure S3A), because Smo is the important intermediary factor in the canonical HH pathway. Tumour spheres formed by shSmo–GL261 cells were not only smaller in size (Figure 5A) but also fewer in number (Figure 5B) than those formed by mock-GL261 cells. Furthermore, ECs had less effect on formation of tumour spheres by shSmo–GL261 cells (Figure 5A, B). Additionally, CD133 was down-regulated in shSmo–GL261 cells, and the level of CD133 in the shSmo–GL261 co-cultured with ECs could not increase to that in the mock-GL261 cells co-cultured with ECs (Figure 5C; see also supplementary material, Figure S3B). Moreover, the expressions of Sox2, Olig2 and Bmi1 were all reduced in shSmo–GL261 cells, on which ECs had no effect (Figure 5D). Allografts were generated from shSmo–GL261 cells and mock-GL261 cells that were injected with or without ECs. ShSmo–GL261 cells generated significantly smaller tumours than mock-GL261 cells, regardless of the presence or not of ECs (Figure 5E; see also supplementary material, Figure S3C). Collectively, these results indicate that the stemness of GL261 is enhanced upon HH pathway activation and suggest that the promotion of GSC-like phenotype by ECs is mediated through the HH pathway.


Endothelial cells promote stem-like phenotype of glioma cells through activating the Hedgehog pathway.

Yan GN, Yang L, Lv YF, Shi Y, Shen LL, Yao XH, Guo QN, Zhang P, Cui YH, Zhang X, Bian XW, Guo DY - J. Pathol. (2014)

Inhibition of Hedgehog pathway hampers the appearance of GSC-like phenotype of glioma cells. As compared to mock-GL261 alone or mock-GL261 cells co-cultured with b.END3, shSmo–GL261 alone or shSmo–GL261 cells co-cultured with b.END3 cells formed smaller tumour spheres (A; scale bar = 100 µm) and fewer tumour spheres (B; *p < 0.05), respectively. CD133 expression of shSmo–GL261 cells was reduced (C) and expressions of Sox2, Olig2 and Bmi1 were significantly reduced (D), respectively, tubulin was used as control. Subcutaneous allografts generated by shSmo–GL261 cells, with or without b.END3 cells, were significantly smaller in volume as compared to mock GL261 cells with or without b.END3 cells (E; *p < 0.05), respectively; −, wild-type GL261 cells; +, Smo-knockdown GL261 cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC4260128&req=5

fig05: Inhibition of Hedgehog pathway hampers the appearance of GSC-like phenotype of glioma cells. As compared to mock-GL261 alone or mock-GL261 cells co-cultured with b.END3, shSmo–GL261 alone or shSmo–GL261 cells co-cultured with b.END3 cells formed smaller tumour spheres (A; scale bar = 100 µm) and fewer tumour spheres (B; *p < 0.05), respectively. CD133 expression of shSmo–GL261 cells was reduced (C) and expressions of Sox2, Olig2 and Bmi1 were significantly reduced (D), respectively, tubulin was used as control. Subcutaneous allografts generated by shSmo–GL261 cells, with or without b.END3 cells, were significantly smaller in volume as compared to mock GL261 cells with or without b.END3 cells (E; *p < 0.05), respectively; −, wild-type GL261 cells; +, Smo-knockdown GL261 cells.
Mentions: To determine whether HH pathway activation mediated the promotion of a GSC-like phenotype, we generated Smo-knockdown GL261 cells (shSmo–GL261; see supplementary material, Figure S3A), because Smo is the important intermediary factor in the canonical HH pathway. Tumour spheres formed by shSmo–GL261 cells were not only smaller in size (Figure 5A) but also fewer in number (Figure 5B) than those formed by mock-GL261 cells. Furthermore, ECs had less effect on formation of tumour spheres by shSmo–GL261 cells (Figure 5A, B). Additionally, CD133 was down-regulated in shSmo–GL261 cells, and the level of CD133 in the shSmo–GL261 co-cultured with ECs could not increase to that in the mock-GL261 cells co-cultured with ECs (Figure 5C; see also supplementary material, Figure S3B). Moreover, the expressions of Sox2, Olig2 and Bmi1 were all reduced in shSmo–GL261 cells, on which ECs had no effect (Figure 5D). Allografts were generated from shSmo–GL261 cells and mock-GL261 cells that were injected with or without ECs. ShSmo–GL261 cells generated significantly smaller tumours than mock-GL261 cells, regardless of the presence or not of ECs (Figure 5E; see also supplementary material, Figure S3C). Collectively, these results indicate that the stemness of GL261 is enhanced upon HH pathway activation and suggest that the promotion of GSC-like phenotype by ECs is mediated through the HH pathway.

Bottom Line: Microenvironmental regulation of cancer stem cells (CSCs) strongly influences the onset and spread of cancer.We observed that CD133(+) GSCs were located closely to Shh(+) endothelial cells in specimens of human glioblastoma multiforme (GBM).Knockdown of Smo in glioma cells led to a significant reduction of their CSC-like phenotype formation in vitro and in vivo.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University and Key Laboratory of Tumour Immunopathology, Ministry of Education of China, Chongqing, 400038, People's Republic of China.

Show MeSH
Related in: MedlinePlus