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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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VEGF-expressing tumor cells show enhanced metastasis. ID8 murine ovarian carcinoma cells, which stably express GFP, were injected i.v. to form pulmonary metastatic lesions. (A) Fresh lung tissue was examined using laser scanning confocal microscopy to detect GFP-positive metastatic tumor cells. After 9 d, considerably more metastatic lesions were visible in lungs of mice injected with cells expressing VEGF (ID8-VEGF-GFP) compared with cells expressing GFP alone (ID8-GFP). (B) Lung weight due to tumor was significantly increased. * indicates P < 0.05; n = 8 each bar. Bar, 1 mm.
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fig2: VEGF-expressing tumor cells show enhanced metastasis. ID8 murine ovarian carcinoma cells, which stably express GFP, were injected i.v. to form pulmonary metastatic lesions. (A) Fresh lung tissue was examined using laser scanning confocal microscopy to detect GFP-positive metastatic tumor cells. After 9 d, considerably more metastatic lesions were visible in lungs of mice injected with cells expressing VEGF (ID8-VEGF-GFP) compared with cells expressing GFP alone (ID8-GFP). (B) Lung weight due to tumor was significantly increased. * indicates P < 0.05; n = 8 each bar. Bar, 1 mm.

Mentions: To evaluate the possibility that endothelial barrier breakdown by VEGF contributes to tumor cell extravasation, we tested ID8 murine ovarian carcinoma cells retrovirally infected to stably express GFP either alone or together with VEGF (Zhang et al., 2002). ID8 cells overexpressing VEGF were previously found to have a metastatic advantage compared with ID8 cells lacking VEGF (Zhang et al., 2002), but it was unclear whether tumor cell extravasation was enhanced. Accordingly, ID8 cells were injected i.v. into the tail vein and tumor metastasis was monitored 9 d later. The VEGF-expressing ID8 cells formed considerably more metastatic lesions in the lung than the cells expressing GFP alone (Fig. 2), suggesting that VEGF contributes to tumor cell extravasation and/or cell proliferation at the metastatic site. Together, these studies suggest that tumor cell extravasation is linked to the ability of VEGF to promote a breakdown in endothelial barrier function.


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)

VEGF-expressing tumor cells show enhanced metastasis. ID8 murine ovarian carcinoma cells, which stably express GFP, were injected i.v. to form pulmonary metastatic lesions. (A) Fresh lung tissue was examined using laser scanning confocal microscopy to detect GFP-positive metastatic tumor cells. After 9 d, considerably more metastatic lesions were visible in lungs of mice injected with cells expressing VEGF (ID8-VEGF-GFP) compared with cells expressing GFP alone (ID8-GFP). (B) Lung weight due to tumor was significantly increased. * indicates P < 0.05; n = 8 each bar. Bar, 1 mm.
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Related In: Results  -  Collection

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

fig2: VEGF-expressing tumor cells show enhanced metastasis. ID8 murine ovarian carcinoma cells, which stably express GFP, were injected i.v. to form pulmonary metastatic lesions. (A) Fresh lung tissue was examined using laser scanning confocal microscopy to detect GFP-positive metastatic tumor cells. After 9 d, considerably more metastatic lesions were visible in lungs of mice injected with cells expressing VEGF (ID8-VEGF-GFP) compared with cells expressing GFP alone (ID8-GFP). (B) Lung weight due to tumor was significantly increased. * indicates P < 0.05; n = 8 each bar. Bar, 1 mm.
Mentions: To evaluate the possibility that endothelial barrier breakdown by VEGF contributes to tumor cell extravasation, we tested ID8 murine ovarian carcinoma cells retrovirally infected to stably express GFP either alone or together with VEGF (Zhang et al., 2002). ID8 cells overexpressing VEGF were previously found to have a metastatic advantage compared with ID8 cells lacking VEGF (Zhang et al., 2002), but it was unclear whether tumor cell extravasation was enhanced. Accordingly, ID8 cells were injected i.v. into the tail vein and tumor metastasis was monitored 9 d later. The VEGF-expressing ID8 cells formed considerably more metastatic lesions in the lung than the cells expressing GFP alone (Fig. 2), suggesting that VEGF contributes to tumor cell extravasation and/or cell proliferation at the metastatic site. Together, these studies suggest that tumor cell extravasation is linked to the ability of VEGF to promote a breakdown in endothelial barrier function.

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