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Heterozygous deficiency of delta-catenin impairs pathological angiogenesis.

DeBusk LM, Boelte K, Min Y, Lin PC - J. Exp. Med. (2010)

Bottom Line: Molecular analysis confirmed a gene dosage effect of delta-catenin on Rho GTPase activity.Moreover, we show that inflammatory cytokines, but not angiogenic factors, regulate delta-catenin expression, and the levels of delta-catenin positively correlate to human lung cancers.Collectively, our data suggest that inflammation, commonly associated with disease conditions, induces delta-catenin expression that specifically regulates pathological, and not physiological, angiogenesis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

ABSTRACT
Vascular and neuronal networks share a similar branching morphology, and emerging evidence implicates common mechanisms in the formation of both systems. delta-Catenin is considered a neuronal catenin regulating neuron cell-cell adhesion and cell motility. Here, we report expression of delta-catenin in vascular endothelium, and show that deletion of only one allele of delta-catenin is sufficient to impair endothelial cell motility and vascular assembly in vitro and pathological angiogenesis in vivo, thereby inhibiting tumor growth and wound healing. In contrast, deletion of one or both allele of delta-catenin had no effects on hormone-induced physiological angiogenesis in the uterus. Molecular analysis confirmed a gene dosage effect of delta-catenin on Rho GTPase activity. Moreover, we show that inflammatory cytokines, but not angiogenic factors, regulate delta-catenin expression, and the levels of delta-catenin positively correlate to human lung cancers. Collectively, our data suggest that inflammation, commonly associated with disease conditions, induces delta-catenin expression that specifically regulates pathological, and not physiological, angiogenesis. Because only pathological angiogenesis is sensitive to decreased levels of delta-catenin, this may provide a good target for antiangiogenic therapy.

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Genetic deletion of δ-catenin in mice impairs pathological angiogenesis in a dose-dependent manner. 3LL tumor cells were injected subcutaneously into sex- and age-matched syngeneic δ-catenin homozygous-, heterozygous-, and wild-type littermates. (A) Tumor growth was measured by caliper for 15 d, and tumor volume was calculated and plotted (n = 10 mice/group; *, P < 0.001). (B) Tumor tissue sections from each group were analyzed by CD31 immunofluorescent staining, and CD31 positive vessels were counted from 10 randomly selected high-power fields under microscopy. Mean and SE were plotted. *, P < 0.05. (C) 6-mm biopsy punches were made in wild-type littermates, δ-catenin heterozygous-, and δ-catenin homozygous- mice. Wound size was measured daily. The percent changes of wound size over the original size were plotted (n = 7 mice/group; *, P < 0.01). (D) The vascular density measurement by vWF staining was performed in wounded tissues on day 3. Mean and SE were plotted. *, P < 0.01.
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fig5: Genetic deletion of δ-catenin in mice impairs pathological angiogenesis in a dose-dependent manner. 3LL tumor cells were injected subcutaneously into sex- and age-matched syngeneic δ-catenin homozygous-, heterozygous-, and wild-type littermates. (A) Tumor growth was measured by caliper for 15 d, and tumor volume was calculated and plotted (n = 10 mice/group; *, P < 0.001). (B) Tumor tissue sections from each group were analyzed by CD31 immunofluorescent staining, and CD31 positive vessels were counted from 10 randomly selected high-power fields under microscopy. Mean and SE were plotted. *, P < 0.05. (C) 6-mm biopsy punches were made in wild-type littermates, δ-catenin heterozygous-, and δ-catenin homozygous- mice. Wound size was measured daily. The percent changes of wound size over the original size were plotted (n = 7 mice/group; *, P < 0.01). (D) The vascular density measurement by vWF staining was performed in wounded tissues on day 3. Mean and SE were plotted. *, P < 0.01.

Mentions: As tumor growth depends on tumor angiogenesis, we therefore investigated the function of δ-catenin in tumor angiogenesis. Murine 3LL tumor cells were implanted in syngeneic δ-catenin homozygous-, heterozygous-, and wild-type littermates. Tumor growth was measured over time. Consistent with the in vitro data on gene dosage of δ-catenin in angiogenesis, we observed a significant retardation in tumor growth in homozygous- mice, as well as in heterozygous- mice, compared with wild-type controls (Fig. 5 A), which correlates to a reduced tumor vascular density in tumors harvested from these mice (Fig. 5 B and Fig. S4). No significant difference in tumor growth and tumor vascular density between the heterozygous- and homozygous- mice was observed, consistent with the observations of endothelial cell motility and vascular structure formation between these two groups. The experiment was repeated twice, and consistent results were achieved.


Heterozygous deficiency of delta-catenin impairs pathological angiogenesis.

DeBusk LM, Boelte K, Min Y, Lin PC - J. Exp. Med. (2010)

Genetic deletion of δ-catenin in mice impairs pathological angiogenesis in a dose-dependent manner. 3LL tumor cells were injected subcutaneously into sex- and age-matched syngeneic δ-catenin homozygous-, heterozygous-, and wild-type littermates. (A) Tumor growth was measured by caliper for 15 d, and tumor volume was calculated and plotted (n = 10 mice/group; *, P < 0.001). (B) Tumor tissue sections from each group were analyzed by CD31 immunofluorescent staining, and CD31 positive vessels were counted from 10 randomly selected high-power fields under microscopy. Mean and SE were plotted. *, P < 0.05. (C) 6-mm biopsy punches were made in wild-type littermates, δ-catenin heterozygous-, and δ-catenin homozygous- mice. Wound size was measured daily. The percent changes of wound size over the original size were plotted (n = 7 mice/group; *, P < 0.01). (D) The vascular density measurement by vWF staining was performed in wounded tissues on day 3. Mean and SE were plotted. *, P < 0.01.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2812534&req=5

fig5: Genetic deletion of δ-catenin in mice impairs pathological angiogenesis in a dose-dependent manner. 3LL tumor cells were injected subcutaneously into sex- and age-matched syngeneic δ-catenin homozygous-, heterozygous-, and wild-type littermates. (A) Tumor growth was measured by caliper for 15 d, and tumor volume was calculated and plotted (n = 10 mice/group; *, P < 0.001). (B) Tumor tissue sections from each group were analyzed by CD31 immunofluorescent staining, and CD31 positive vessels were counted from 10 randomly selected high-power fields under microscopy. Mean and SE were plotted. *, P < 0.05. (C) 6-mm biopsy punches were made in wild-type littermates, δ-catenin heterozygous-, and δ-catenin homozygous- mice. Wound size was measured daily. The percent changes of wound size over the original size were plotted (n = 7 mice/group; *, P < 0.01). (D) The vascular density measurement by vWF staining was performed in wounded tissues on day 3. Mean and SE were plotted. *, P < 0.01.
Mentions: As tumor growth depends on tumor angiogenesis, we therefore investigated the function of δ-catenin in tumor angiogenesis. Murine 3LL tumor cells were implanted in syngeneic δ-catenin homozygous-, heterozygous-, and wild-type littermates. Tumor growth was measured over time. Consistent with the in vitro data on gene dosage of δ-catenin in angiogenesis, we observed a significant retardation in tumor growth in homozygous- mice, as well as in heterozygous- mice, compared with wild-type controls (Fig. 5 A), which correlates to a reduced tumor vascular density in tumors harvested from these mice (Fig. 5 B and Fig. S4). No significant difference in tumor growth and tumor vascular density between the heterozygous- and homozygous- mice was observed, consistent with the observations of endothelial cell motility and vascular structure formation between these two groups. The experiment was repeated twice, and consistent results were achieved.

Bottom Line: Molecular analysis confirmed a gene dosage effect of delta-catenin on Rho GTPase activity.Moreover, we show that inflammatory cytokines, but not angiogenic factors, regulate delta-catenin expression, and the levels of delta-catenin positively correlate to human lung cancers.Collectively, our data suggest that inflammation, commonly associated with disease conditions, induces delta-catenin expression that specifically regulates pathological, and not physiological, angiogenesis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

ABSTRACT
Vascular and neuronal networks share a similar branching morphology, and emerging evidence implicates common mechanisms in the formation of both systems. delta-Catenin is considered a neuronal catenin regulating neuron cell-cell adhesion and cell motility. Here, we report expression of delta-catenin in vascular endothelium, and show that deletion of only one allele of delta-catenin is sufficient to impair endothelial cell motility and vascular assembly in vitro and pathological angiogenesis in vivo, thereby inhibiting tumor growth and wound healing. In contrast, deletion of one or both allele of delta-catenin had no effects on hormone-induced physiological angiogenesis in the uterus. Molecular analysis confirmed a gene dosage effect of delta-catenin on Rho GTPase activity. Moreover, we show that inflammatory cytokines, but not angiogenic factors, regulate delta-catenin expression, and the levels of delta-catenin positively correlate to human lung cancers. Collectively, our data suggest that inflammation, commonly associated with disease conditions, induces delta-catenin expression that specifically regulates pathological, and not physiological, angiogenesis. Because only pathological angiogenesis is sensitive to decreased levels of delta-catenin, this may provide a good target for antiangiogenic therapy.

Show MeSH
Related in: MedlinePlus