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Expression of platelet-derived growth factor receptor β is maintained by Prox1 in lymphatic endothelial cells and is required for tumor lymphangiogenesis.

Miyazaki H, Yoshimatsu Y, Akatsu Y, Mishima K, Fukayama M, Watabe T, Miyazono K - Cancer Sci. (2014)

Bottom Line: Furthermore, we found that PDGF signals play important roles in inflammatory lymphangiogenesis in a chronic aseptic peritonitis model.Intraperitoneal administration of imatinib, a potent inhibitor of PDGFRβ, and transduction of PDGFRβ/Fc chimeric protein by an adenoviral system both reduced inflammatory lymphangiogenesis induced by thioglycollate in mice.We also found that the expression of PDGFRβ/Fc reduced tumor lymphangiogenesis in a BxPC3 human pancreatic cancer xenograft model.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Human Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

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Effects of platelet-derived growth factor receptor (PDGFR) β/Fc decoy receptor on inflammatory lymphangiogenesis in the diaphragm. (a) Structure of PDGFRβ (top) and PDGFRβ/Fc chimeric receptor (bottom). a.a., amino acids; TM, transmembrane domain. (b) Repeated i.p. injection of inflammation-inducing thioglycollate led to formation of lymphangiogenic plaques on the peritoneal side of the murine diaphragm. Adenoviruses encoding control-Fc or PDGFRβ/Fc were also i.p. injected repeatedly, and the diaphragms from mice killed after 16 days were subjected to whole-mount immunostaining with anti-LYVE-1 antibody. (c) Densities of LYVE-1-positive diaphragmatic lymphatic vessels were measured in each defined area, and values are presented as the ratio of LYVE-1-positive area to total area of the field. Error bars represent SE. **P < 0.01 (evaluated by Student's t-test).
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fig06: Effects of platelet-derived growth factor receptor (PDGFR) β/Fc decoy receptor on inflammatory lymphangiogenesis in the diaphragm. (a) Structure of PDGFRβ (top) and PDGFRβ/Fc chimeric receptor (bottom). a.a., amino acids; TM, transmembrane domain. (b) Repeated i.p. injection of inflammation-inducing thioglycollate led to formation of lymphangiogenic plaques on the peritoneal side of the murine diaphragm. Adenoviruses encoding control-Fc or PDGFRβ/Fc were also i.p. injected repeatedly, and the diaphragms from mice killed after 16 days were subjected to whole-mount immunostaining with anti-LYVE-1 antibody. (c) Densities of LYVE-1-positive diaphragmatic lymphatic vessels were measured in each defined area, and values are presented as the ratio of LYVE-1-positive area to total area of the field. Error bars represent SE. **P < 0.01 (evaluated by Student's t-test).

Mentions: Imatinib is a selective inhibitor for PDGFRβ tyrosine kinase, but it also has multiple targets such as c-Kit and v-Abl at low doses and VEGFR3, -R2 and, -R1 at high doses.24 Therefore, the inhibitory effects of imatinib on inflammatory lymphangiogenesis may have been caused in a PDGFRβ-independent fashion. In order to target PDGF signals more specifically, we generated adenoviruses encoding PDGFRβ/Fc, which consists of the extracellular domain of PDGFRβ and Fc moiety of human IgG (Fig.6a). Addition of the conditioned medium containing PDGFRβ/Fc decreased the PDGF-BB-induced Erk phosphorylation in HDLECs (unpublished data). Adenoviruses containing PDGFRβ/Fc or control-Fc were injected into mice twice a week during the 16-day inflammatory assay period. Compared to control diaphragms from mice injected with control-Fc, those from PDGFRβ/Fc-injected mice showed decreased LYVE-1-positive areas on the diaphragm (Fig.6b,c). Taken together with the assay using imatinib, these findings suggest that endogenous PDGF signals contribute to inflammatory lymphangiogenesis in the diaphragm.


Expression of platelet-derived growth factor receptor β is maintained by Prox1 in lymphatic endothelial cells and is required for tumor lymphangiogenesis.

Miyazaki H, Yoshimatsu Y, Akatsu Y, Mishima K, Fukayama M, Watabe T, Miyazono K - Cancer Sci. (2014)

Effects of platelet-derived growth factor receptor (PDGFR) β/Fc decoy receptor on inflammatory lymphangiogenesis in the diaphragm. (a) Structure of PDGFRβ (top) and PDGFRβ/Fc chimeric receptor (bottom). a.a., amino acids; TM, transmembrane domain. (b) Repeated i.p. injection of inflammation-inducing thioglycollate led to formation of lymphangiogenic plaques on the peritoneal side of the murine diaphragm. Adenoviruses encoding control-Fc or PDGFRβ/Fc were also i.p. injected repeatedly, and the diaphragms from mice killed after 16 days were subjected to whole-mount immunostaining with anti-LYVE-1 antibody. (c) Densities of LYVE-1-positive diaphragmatic lymphatic vessels were measured in each defined area, and values are presented as the ratio of LYVE-1-positive area to total area of the field. Error bars represent SE. **P < 0.01 (evaluated by Student's t-test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4462385&req=5

fig06: Effects of platelet-derived growth factor receptor (PDGFR) β/Fc decoy receptor on inflammatory lymphangiogenesis in the diaphragm. (a) Structure of PDGFRβ (top) and PDGFRβ/Fc chimeric receptor (bottom). a.a., amino acids; TM, transmembrane domain. (b) Repeated i.p. injection of inflammation-inducing thioglycollate led to formation of lymphangiogenic plaques on the peritoneal side of the murine diaphragm. Adenoviruses encoding control-Fc or PDGFRβ/Fc were also i.p. injected repeatedly, and the diaphragms from mice killed after 16 days were subjected to whole-mount immunostaining with anti-LYVE-1 antibody. (c) Densities of LYVE-1-positive diaphragmatic lymphatic vessels were measured in each defined area, and values are presented as the ratio of LYVE-1-positive area to total area of the field. Error bars represent SE. **P < 0.01 (evaluated by Student's t-test).
Mentions: Imatinib is a selective inhibitor for PDGFRβ tyrosine kinase, but it also has multiple targets such as c-Kit and v-Abl at low doses and VEGFR3, -R2 and, -R1 at high doses.24 Therefore, the inhibitory effects of imatinib on inflammatory lymphangiogenesis may have been caused in a PDGFRβ-independent fashion. In order to target PDGF signals more specifically, we generated adenoviruses encoding PDGFRβ/Fc, which consists of the extracellular domain of PDGFRβ and Fc moiety of human IgG (Fig.6a). Addition of the conditioned medium containing PDGFRβ/Fc decreased the PDGF-BB-induced Erk phosphorylation in HDLECs (unpublished data). Adenoviruses containing PDGFRβ/Fc or control-Fc were injected into mice twice a week during the 16-day inflammatory assay period. Compared to control diaphragms from mice injected with control-Fc, those from PDGFRβ/Fc-injected mice showed decreased LYVE-1-positive areas on the diaphragm (Fig.6b,c). Taken together with the assay using imatinib, these findings suggest that endogenous PDGF signals contribute to inflammatory lymphangiogenesis in the diaphragm.

Bottom Line: Furthermore, we found that PDGF signals play important roles in inflammatory lymphangiogenesis in a chronic aseptic peritonitis model.Intraperitoneal administration of imatinib, a potent inhibitor of PDGFRβ, and transduction of PDGFRβ/Fc chimeric protein by an adenoviral system both reduced inflammatory lymphangiogenesis induced by thioglycollate in mice.We also found that the expression of PDGFRβ/Fc reduced tumor lymphangiogenesis in a BxPC3 human pancreatic cancer xenograft model.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Human Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Show MeSH
Related in: MedlinePlus