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Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis.

Weis S, Cui J, Barnes L, Cheresh D - J. Cell Biol. (2004)

Bottom Line: VEGF is unique among angiogenic growth factors because it disrupts endothelial barrier function.We found a dramatic reduction in tumor cell extravasation in lungs or livers of mice lacking Src or Yes.Therefore, disrupting Src signaling preserves host endothelial barrier function providing a novel host-targeted approach to control metastatic disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.

ABSTRACT
VEGF is unique among angiogenic growth factors because it disrupts endothelial barrier function. Therefore, we considered whether this property of VEGF might contribute to tumor cell extravasation and metastasis. To test this, mice lacking the Src family kinases Src or Yes, which maintain endothelial barrier function in the presence of VEGF, were injected intravenously with VEGF-expressing tumor cells. We found a dramatic reduction in tumor cell extravasation in lungs or livers of mice lacking Src or Yes. At the molecular level, VEGF compromises the endothelial barrier by disrupting a VE-cadherin-beta-catenin complex in lung endothelium from wild-type, but not Yes-deficient, mice. Disrupting the endothelial barrier directly with anti-VE-cadherin both amplifies metastasis in normal mice and overcomes the genetic resistance in Yes-deficient mice. Pharmacological blockade of VEGF, VEGFR-2, or Src stabilizes endothelial barrier function and suppresses tumor cell extravasation in vivo. Therefore, disrupting Src signaling preserves host endothelial barrier function providing a novel host-targeted approach to control metastatic disease.

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Disruption of cadherin-mediated adhesion enhances tumor cell extravasation. (A) Direct i.v. injection of VEGF induces rapid and transient dissociation of β-catenin from VE-cadherin in lung from wild-type, but not Yes-deficient mice, determined by immunoprecipitation and immunoblotting of mouse lung homogenates. Representative data from three experiments are shown. (B) Treating mice before tumor cell inoculation with VE-cadherin–disrupting antibody BV13 induces vascular permeability, facilitates CT26 tumor cell extravasation, and increases metastases. VE-cadherin antibody E4G10 which does not produce permeability has no impact on metastasis. Tumor burden represents increase in lung/heart weight ratio over control. * indicates P < 0.05; n = 8 each bar (A) and n = 4 each bar (B).
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fig4: Disruption of cadherin-mediated adhesion enhances tumor cell extravasation. (A) Direct i.v. injection of VEGF induces rapid and transient dissociation of β-catenin from VE-cadherin in lung from wild-type, but not Yes-deficient mice, determined by immunoprecipitation and immunoblotting of mouse lung homogenates. Representative data from three experiments are shown. (B) Treating mice before tumor cell inoculation with VE-cadherin–disrupting antibody BV13 induces vascular permeability, facilitates CT26 tumor cell extravasation, and increases metastases. VE-cadherin antibody E4G10 which does not produce permeability has no impact on metastasis. Tumor burden represents increase in lung/heart weight ratio over control. * indicates P < 0.05; n = 8 each bar (A) and n = 4 each bar (B).

Mentions: Recently, we showed that during ischemic injury, VEGF-mediated vascular permeability depends on Src kinase-induced uncoupling of VE-cadherin–β-catenin containing junctions in vivo (Weis et al., 2004). Therefore, we evaluated the possibility that VEGF-expressing tumor cells circulating in the lung may compromise the vascular barrier by disrupting the VE-cadherin–β-catenin complex within the lung vasculature. Mice were injected i.v. with VEGF and lung lysates were subjected to immunoprecipitation and immunoblotting to detect the VE-cadherin–β-catenin complex. 5 min after VEGF stimulation, we observed a transient but consistent decrease in the lung endothelial cell VE-cadherin–β-catenin complex (Fig. 4 A). In contrast, this VE-cadherin–β-catenin complex did not dissociate after VEGF treatment in Yes-deficient mice (Fig. 4 A), which are resistant to the permeability-promoting effects of VEGF (Eliceiri et al., 1999) and to tumor cell extravasation (Fig. 3 A). These data not only confirm a role for Src kinases downstream of VEGF in the regulation of cadherin-mediated endothelial junctional barrier function, but help to explain the resistance these animals display toward tumor cell extravasation.


Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis.

Weis S, Cui J, Barnes L, Cheresh D - J. Cell Biol. (2004)

Disruption of cadherin-mediated adhesion enhances tumor cell extravasation. (A) Direct i.v. injection of VEGF induces rapid and transient dissociation of β-catenin from VE-cadherin in lung from wild-type, but not Yes-deficient mice, determined by immunoprecipitation and immunoblotting of mouse lung homogenates. Representative data from three experiments are shown. (B) Treating mice before tumor cell inoculation with VE-cadherin–disrupting antibody BV13 induces vascular permeability, facilitates CT26 tumor cell extravasation, and increases metastases. VE-cadherin antibody E4G10 which does not produce permeability has no impact on metastasis. Tumor burden represents increase in lung/heart weight ratio over control. * indicates P < 0.05; n = 8 each bar (A) and n = 4 each bar (B).
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Related In: Results  -  Collection

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fig4: Disruption of cadherin-mediated adhesion enhances tumor cell extravasation. (A) Direct i.v. injection of VEGF induces rapid and transient dissociation of β-catenin from VE-cadherin in lung from wild-type, but not Yes-deficient mice, determined by immunoprecipitation and immunoblotting of mouse lung homogenates. Representative data from three experiments are shown. (B) Treating mice before tumor cell inoculation with VE-cadherin–disrupting antibody BV13 induces vascular permeability, facilitates CT26 tumor cell extravasation, and increases metastases. VE-cadherin antibody E4G10 which does not produce permeability has no impact on metastasis. Tumor burden represents increase in lung/heart weight ratio over control. * indicates P < 0.05; n = 8 each bar (A) and n = 4 each bar (B).
Mentions: Recently, we showed that during ischemic injury, VEGF-mediated vascular permeability depends on Src kinase-induced uncoupling of VE-cadherin–β-catenin containing junctions in vivo (Weis et al., 2004). Therefore, we evaluated the possibility that VEGF-expressing tumor cells circulating in the lung may compromise the vascular barrier by disrupting the VE-cadherin–β-catenin complex within the lung vasculature. Mice were injected i.v. with VEGF and lung lysates were subjected to immunoprecipitation and immunoblotting to detect the VE-cadherin–β-catenin complex. 5 min after VEGF stimulation, we observed a transient but consistent decrease in the lung endothelial cell VE-cadherin–β-catenin complex (Fig. 4 A). In contrast, this VE-cadherin–β-catenin complex did not dissociate after VEGF treatment in Yes-deficient mice (Fig. 4 A), which are resistant to the permeability-promoting effects of VEGF (Eliceiri et al., 1999) and to tumor cell extravasation (Fig. 3 A). These data not only confirm a role for Src kinases downstream of VEGF in the regulation of cadherin-mediated endothelial junctional barrier function, but help to explain the resistance these animals display toward tumor cell extravasation.

Bottom Line: VEGF is unique among angiogenic growth factors because it disrupts endothelial barrier function.We found a dramatic reduction in tumor cell extravasation in lungs or livers of mice lacking Src or Yes.Therefore, disrupting Src signaling preserves host endothelial barrier function providing a novel host-targeted approach to control metastatic disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.

ABSTRACT
VEGF is unique among angiogenic growth factors because it disrupts endothelial barrier function. Therefore, we considered whether this property of VEGF might contribute to tumor cell extravasation and metastasis. To test this, mice lacking the Src family kinases Src or Yes, which maintain endothelial barrier function in the presence of VEGF, were injected intravenously with VEGF-expressing tumor cells. We found a dramatic reduction in tumor cell extravasation in lungs or livers of mice lacking Src or Yes. At the molecular level, VEGF compromises the endothelial barrier by disrupting a VE-cadherin-beta-catenin complex in lung endothelium from wild-type, but not Yes-deficient, mice. Disrupting the endothelial barrier directly with anti-VE-cadherin both amplifies metastasis in normal mice and overcomes the genetic resistance in Yes-deficient mice. Pharmacological blockade of VEGF, VEGFR-2, or Src stabilizes endothelial barrier function and suppresses tumor cell extravasation in vivo. Therefore, disrupting Src signaling preserves host endothelial barrier function providing a novel host-targeted approach to control metastatic disease.

Show MeSH
Related in: MedlinePlus