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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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Pharmacological Src, Flk, or VEGF blockade suppresses tumor cell extravasation. (A) Pretreatment with VEGF inhibitor Cyclo-VEGI provides a similar extent of protection from pulmonary metastases as Src or Flk inhibition, further suggesting the permeability-inducing effects of VEGF contribute to tumor cell extravasation. (B) VEGF receptor 2 signaling is required for metastasis of CT26 cells because a single pretreatment with Flk inhibitor SU1498 reduces lung tumor burden after 12 d. (C) Pretreatment with Src inhibitor provides a dose-dependent blockade of VEGF-induced vascular leak in the skin evaluated using the Miles assay. (D) Src inhibitor treatment administered twice daily during days 0–3 after i.v. introduction of CT26 or D121 cells significantly reduces lung tumor burden after 12 d. (E) Preventing VEGF-induced endothelial barrier breakdown via VEGF, Flk, or Src blockade preserves cadherin-mediated endothelial cell adhesion and limits tumor cell extravasation. Tumor burden represents mean ± SEM for increase in lung/heart weight ratio over control. * indicates P < 0.05; n = 8 each bar (A, B, and D); n = 4 each bar (C).
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fig5: Pharmacological Src, Flk, or VEGF blockade suppresses tumor cell extravasation. (A) Pretreatment with VEGF inhibitor Cyclo-VEGI provides a similar extent of protection from pulmonary metastases as Src or Flk inhibition, further suggesting the permeability-inducing effects of VEGF contribute to tumor cell extravasation. (B) VEGF receptor 2 signaling is required for metastasis of CT26 cells because a single pretreatment with Flk inhibitor SU1498 reduces lung tumor burden after 12 d. (C) Pretreatment with Src inhibitor provides a dose-dependent blockade of VEGF-induced vascular leak in the skin evaluated using the Miles assay. (D) Src inhibitor treatment administered twice daily during days 0–3 after i.v. introduction of CT26 or D121 cells significantly reduces lung tumor burden after 12 d. (E) Preventing VEGF-induced endothelial barrier breakdown via VEGF, Flk, or Src blockade preserves cadherin-mediated endothelial cell adhesion and limits tumor cell extravasation. Tumor burden represents mean ± SEM for increase in lung/heart weight ratio over control. * indicates P < 0.05; n = 8 each bar (A, B, and D); n = 4 each bar (C).

Mentions: If VEGF signaling potentiates endothelial barrier breakdown, then pharmacological blockade of VEGF or its downstream effectors might reduce tumor cell extravasation. Thus, we tested if blocking VEGF signaling during the first 2 d after i.v. administration of tumor cells would impact extravasation. We found that treating mice with the VEGF inhibitor Cyclo-VEGI reduced pulmonary metastasis by 47% (Fig. 5 A, P = 0.01), suggesting that an early step in tumor cell extravasation is sensitive to pharmacological inhibition of VEGF.


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)

Pharmacological Src, Flk, or VEGF blockade suppresses tumor cell extravasation. (A) Pretreatment with VEGF inhibitor Cyclo-VEGI provides a similar extent of protection from pulmonary metastases as Src or Flk inhibition, further suggesting the permeability-inducing effects of VEGF contribute to tumor cell extravasation. (B) VEGF receptor 2 signaling is required for metastasis of CT26 cells because a single pretreatment with Flk inhibitor SU1498 reduces lung tumor burden after 12 d. (C) Pretreatment with Src inhibitor provides a dose-dependent blockade of VEGF-induced vascular leak in the skin evaluated using the Miles assay. (D) Src inhibitor treatment administered twice daily during days 0–3 after i.v. introduction of CT26 or D121 cells significantly reduces lung tumor burden after 12 d. (E) Preventing VEGF-induced endothelial barrier breakdown via VEGF, Flk, or Src blockade preserves cadherin-mediated endothelial cell adhesion and limits tumor cell extravasation. Tumor burden represents mean ± SEM for increase in lung/heart weight ratio over control. * indicates P < 0.05; n = 8 each bar (A, B, and D); n = 4 each bar (C).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172541&req=5

fig5: Pharmacological Src, Flk, or VEGF blockade suppresses tumor cell extravasation. (A) Pretreatment with VEGF inhibitor Cyclo-VEGI provides a similar extent of protection from pulmonary metastases as Src or Flk inhibition, further suggesting the permeability-inducing effects of VEGF contribute to tumor cell extravasation. (B) VEGF receptor 2 signaling is required for metastasis of CT26 cells because a single pretreatment with Flk inhibitor SU1498 reduces lung tumor burden after 12 d. (C) Pretreatment with Src inhibitor provides a dose-dependent blockade of VEGF-induced vascular leak in the skin evaluated using the Miles assay. (D) Src inhibitor treatment administered twice daily during days 0–3 after i.v. introduction of CT26 or D121 cells significantly reduces lung tumor burden after 12 d. (E) Preventing VEGF-induced endothelial barrier breakdown via VEGF, Flk, or Src blockade preserves cadherin-mediated endothelial cell adhesion and limits tumor cell extravasation. Tumor burden represents mean ± SEM for increase in lung/heart weight ratio over control. * indicates P < 0.05; n = 8 each bar (A, B, and D); n = 4 each bar (C).
Mentions: If VEGF signaling potentiates endothelial barrier breakdown, then pharmacological blockade of VEGF or its downstream effectors might reduce tumor cell extravasation. Thus, we tested if blocking VEGF signaling during the first 2 d after i.v. administration of tumor cells would impact extravasation. We found that treating mice with the VEGF inhibitor Cyclo-VEGI reduced pulmonary metastasis by 47% (Fig. 5 A, P = 0.01), suggesting that an early step in tumor cell extravasation is sensitive to pharmacological inhibition of VEGF.

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