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Tumor-derived microvesicles induce proangiogenic phenotype in endothelial cells via endocytosis.

Kawamoto T, Ohga N, Akiyama K, Hirata N, Kitahara S, Maishi N, Osawa T, Yamamoto K, Kondoh M, Shindoh M, Hida Y, Hida K - PLoS ONE (2012)

Bottom Line: In addition, we found that TMV promoted random motility and tube formation through the activation of the phosphoinositide 3-kinase/Akt pathway in NEC.Moreover, the effects induced by TMV were inhibited by the endocytosis inhibitor dynasore.Our results indicate that TMV could confer proangiogenic properties to NEC partly via endocytosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Vascular Biology, Graduate School of Dental Medicine, University of Hokkaido, Sapporo, Hokkaido, Japan.

ABSTRACT

Background: Increasing evidence indicates that tumor endothelial cells (TEC) differ from normal endothelial cells (NEC). Our previous reports also showed that TEC were different from NEC. For example, TEC have chromosomal abnormality and proangiogenic properties such as high motility and proliferative activity. However, the mechanism by which TEC acquire a specific character remains unclear. To investigate this mechanism, we focused on tumor-derived microvesicles (TMV). Recent studies have shown that TMV contain numerous types of bioactive molecules and affect normal stromal cells in the tumor microenvironment. However, most of the functional mechanisms of TMV remain unclear.

Methodology/principal findings: Here we showed that TMV isolated from tumor cells were taken up by NEC through endocytosis. In addition, we found that TMV promoted random motility and tube formation through the activation of the phosphoinositide 3-kinase/Akt pathway in NEC. Moreover, the effects induced by TMV were inhibited by the endocytosis inhibitor dynasore. Our results indicate that TMV could confer proangiogenic properties to NEC partly via endocytosis.

Conclusion: We for the first time showed that endocytosis of TMV contributes to tumor angiogenesis. These findings offer new insights into cancer therapies and the crosstalk between tumor and endothelial cells mediated by TMV in the tumor microenvironment.

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TMV promote random motility and tube formation in NEC.Time-lapse observation revealed that TMV promote random motility in NEC. When treated by the endocytosis inhibitor dynasore, cell motility was not stimulated anymore. (A) Migrated trajectories of TMV-treated NEC (with/without 50 µM dynasore) were plotted and velocity was calculated using ImageJ. (B) The results are presented as mean velocities ± SE (DMSO; n = 15, DMSO+TMV; n = 15, dynasore; n = 15, dynasore+TMV; n = 15). *P<0.01. TMV also promote tube formation in NEC. Dynasore canceled increase of tube formation even in NEC cultured with TMV. (C) Phase-contrast images of control and TMV-treated NEC (with/without 50 µM dynasore) cultured on a matrigel. Bar = 100 µm. Capillary-like structure enhanced with TMV. Total length of capillary-like tubes was analyzed using ImageJ. (D) The results are presented as mean tube length per field ± SE. (DMSO; n = 10, TMV; n = 10, dynasore; n = 10, dynasore+TMV; n = 10). *P<0.01.
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pone-0034045-g003: TMV promote random motility and tube formation in NEC.Time-lapse observation revealed that TMV promote random motility in NEC. When treated by the endocytosis inhibitor dynasore, cell motility was not stimulated anymore. (A) Migrated trajectories of TMV-treated NEC (with/without 50 µM dynasore) were plotted and velocity was calculated using ImageJ. (B) The results are presented as mean velocities ± SE (DMSO; n = 15, DMSO+TMV; n = 15, dynasore; n = 15, dynasore+TMV; n = 15). *P<0.01. TMV also promote tube formation in NEC. Dynasore canceled increase of tube formation even in NEC cultured with TMV. (C) Phase-contrast images of control and TMV-treated NEC (with/without 50 µM dynasore) cultured on a matrigel. Bar = 100 µm. Capillary-like structure enhanced with TMV. Total length of capillary-like tubes was analyzed using ImageJ. (D) The results are presented as mean tube length per field ± SE. (DMSO; n = 10, TMV; n = 10, dynasore; n = 10, dynasore+TMV; n = 10). *P<0.01.

Mentions: We have shown that TEC have higher motility, which is important for angiogenesis, than NEC [8]. To analyze the effects of TMV on NEC, they were treated with TMV (50 µg/ml) for 12 h, and the random motility of cells was traced for 12 h using time-lapse videoscopy (Figure 3A).


Tumor-derived microvesicles induce proangiogenic phenotype in endothelial cells via endocytosis.

Kawamoto T, Ohga N, Akiyama K, Hirata N, Kitahara S, Maishi N, Osawa T, Yamamoto K, Kondoh M, Shindoh M, Hida Y, Hida K - PLoS ONE (2012)

TMV promote random motility and tube formation in NEC.Time-lapse observation revealed that TMV promote random motility in NEC. When treated by the endocytosis inhibitor dynasore, cell motility was not stimulated anymore. (A) Migrated trajectories of TMV-treated NEC (with/without 50 µM dynasore) were plotted and velocity was calculated using ImageJ. (B) The results are presented as mean velocities ± SE (DMSO; n = 15, DMSO+TMV; n = 15, dynasore; n = 15, dynasore+TMV; n = 15). *P<0.01. TMV also promote tube formation in NEC. Dynasore canceled increase of tube formation even in NEC cultured with TMV. (C) Phase-contrast images of control and TMV-treated NEC (with/without 50 µM dynasore) cultured on a matrigel. Bar = 100 µm. Capillary-like structure enhanced with TMV. Total length of capillary-like tubes was analyzed using ImageJ. (D) The results are presented as mean tube length per field ± SE. (DMSO; n = 10, TMV; n = 10, dynasore; n = 10, dynasore+TMV; n = 10). *P<0.01.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3316594&req=5

pone-0034045-g003: TMV promote random motility and tube formation in NEC.Time-lapse observation revealed that TMV promote random motility in NEC. When treated by the endocytosis inhibitor dynasore, cell motility was not stimulated anymore. (A) Migrated trajectories of TMV-treated NEC (with/without 50 µM dynasore) were plotted and velocity was calculated using ImageJ. (B) The results are presented as mean velocities ± SE (DMSO; n = 15, DMSO+TMV; n = 15, dynasore; n = 15, dynasore+TMV; n = 15). *P<0.01. TMV also promote tube formation in NEC. Dynasore canceled increase of tube formation even in NEC cultured with TMV. (C) Phase-contrast images of control and TMV-treated NEC (with/without 50 µM dynasore) cultured on a matrigel. Bar = 100 µm. Capillary-like structure enhanced with TMV. Total length of capillary-like tubes was analyzed using ImageJ. (D) The results are presented as mean tube length per field ± SE. (DMSO; n = 10, TMV; n = 10, dynasore; n = 10, dynasore+TMV; n = 10). *P<0.01.
Mentions: We have shown that TEC have higher motility, which is important for angiogenesis, than NEC [8]. To analyze the effects of TMV on NEC, they were treated with TMV (50 µg/ml) for 12 h, and the random motility of cells was traced for 12 h using time-lapse videoscopy (Figure 3A).

Bottom Line: In addition, we found that TMV promoted random motility and tube formation through the activation of the phosphoinositide 3-kinase/Akt pathway in NEC.Moreover, the effects induced by TMV were inhibited by the endocytosis inhibitor dynasore.Our results indicate that TMV could confer proangiogenic properties to NEC partly via endocytosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Vascular Biology, Graduate School of Dental Medicine, University of Hokkaido, Sapporo, Hokkaido, Japan.

ABSTRACT

Background: Increasing evidence indicates that tumor endothelial cells (TEC) differ from normal endothelial cells (NEC). Our previous reports also showed that TEC were different from NEC. For example, TEC have chromosomal abnormality and proangiogenic properties such as high motility and proliferative activity. However, the mechanism by which TEC acquire a specific character remains unclear. To investigate this mechanism, we focused on tumor-derived microvesicles (TMV). Recent studies have shown that TMV contain numerous types of bioactive molecules and affect normal stromal cells in the tumor microenvironment. However, most of the functional mechanisms of TMV remain unclear.

Methodology/principal findings: Here we showed that TMV isolated from tumor cells were taken up by NEC through endocytosis. In addition, we found that TMV promoted random motility and tube formation through the activation of the phosphoinositide 3-kinase/Akt pathway in NEC. Moreover, the effects induced by TMV were inhibited by the endocytosis inhibitor dynasore. Our results indicate that TMV could confer proangiogenic properties to NEC partly via endocytosis.

Conclusion: We for the first time showed that endocytosis of TMV contributes to tumor angiogenesis. These findings offer new insights into cancer therapies and the crosstalk between tumor and endothelial cells mediated by TMV in the tumor microenvironment.

Show MeSH
Related in: MedlinePlus