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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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Gene-targeted deletion of individual Src kinases protects against tumor cell extravasation. (A–C) Tumor burden, computed as the increase in lung/heart weight ratio over that for normal mice, was measured 12 d after i.v. inoculation with metastatic tumor cells. Mice lacking Src (A) or Yes (B and C) are protected from experimental pulmonary metastasis of CT26 (A and B) or D121 (C) cells. (D) This phenomenon is not specific to the lung, because Yes-deficient mice are also protected from experimental hepatic metastasis of CT26 or D121 cells. (E) Growth of primary tumors on the flank is not different between genotypes for CT26 or D121 cells. (F) Mice lacking Fyn, which show a normal vascular permeability response to VEGF, are not protected from metastasis. * indicates P < 0.05; n = 8 each bar. Bar, 1 mm.
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fig3: Gene-targeted deletion of individual Src kinases protects against tumor cell extravasation. (A–C) Tumor burden, computed as the increase in lung/heart weight ratio over that for normal mice, was measured 12 d after i.v. inoculation with metastatic tumor cells. Mice lacking Src (A) or Yes (B and C) are protected from experimental pulmonary metastasis of CT26 (A and B) or D121 (C) cells. (D) This phenomenon is not specific to the lung, because Yes-deficient mice are also protected from experimental hepatic metastasis of CT26 or D121 cells. (E) Growth of primary tumors on the flank is not different between genotypes for CT26 or D121 cells. (F) Mice lacking Fyn, which show a normal vascular permeability response to VEGF, are not protected from metastasis. * indicates P < 0.05; n = 8 each bar. Bar, 1 mm.

Mentions: We demonstrated previously that Src- or Yes-deficient mice or normal mice treated with pharmacological Src inhibitors fail to undergo VEGF-dependent vascular permeability yet show normal VEGF-mediated angiogenesis (Eliceiri et al., 1999). Thus, these mice allow us to evaluate the role that VEGF-mediated vascular permeability plays in tumor cell extravasation in vivo. Src- or Yes-deficient mice showed significantly diminished CT26 or D121 Lewis Lung carcinoma metastatic lesions in the lung compared with wild-type littermates (Fig. 3, A–C). In a second metastatic model, CT26 or D121 cells were injected beneath the spleen capsule followed by splenectomy, which ultimately results in hepatic metastatic lesions (Xiang et al., 1997). Consistent with the lung model, Yes-deficient mice showed sharply reduced hepatic metastases compared with control animals for either cell line (Fig. 3 D).


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)

Gene-targeted deletion of individual Src kinases protects against tumor cell extravasation. (A–C) Tumor burden, computed as the increase in lung/heart weight ratio over that for normal mice, was measured 12 d after i.v. inoculation with metastatic tumor cells. Mice lacking Src (A) or Yes (B and C) are protected from experimental pulmonary metastasis of CT26 (A and B) or D121 (C) cells. (D) This phenomenon is not specific to the lung, because Yes-deficient mice are also protected from experimental hepatic metastasis of CT26 or D121 cells. (E) Growth of primary tumors on the flank is not different between genotypes for CT26 or D121 cells. (F) Mice lacking Fyn, which show a normal vascular permeability response to VEGF, are not protected from metastasis. * indicates P < 0.05; n = 8 each bar. Bar, 1 mm.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Gene-targeted deletion of individual Src kinases protects against tumor cell extravasation. (A–C) Tumor burden, computed as the increase in lung/heart weight ratio over that for normal mice, was measured 12 d after i.v. inoculation with metastatic tumor cells. Mice lacking Src (A) or Yes (B and C) are protected from experimental pulmonary metastasis of CT26 (A and B) or D121 (C) cells. (D) This phenomenon is not specific to the lung, because Yes-deficient mice are also protected from experimental hepatic metastasis of CT26 or D121 cells. (E) Growth of primary tumors on the flank is not different between genotypes for CT26 or D121 cells. (F) Mice lacking Fyn, which show a normal vascular permeability response to VEGF, are not protected from metastasis. * indicates P < 0.05; n = 8 each bar. Bar, 1 mm.
Mentions: We demonstrated previously that Src- or Yes-deficient mice or normal mice treated with pharmacological Src inhibitors fail to undergo VEGF-dependent vascular permeability yet show normal VEGF-mediated angiogenesis (Eliceiri et al., 1999). Thus, these mice allow us to evaluate the role that VEGF-mediated vascular permeability plays in tumor cell extravasation in vivo. Src- or Yes-deficient mice showed significantly diminished CT26 or D121 Lewis Lung carcinoma metastatic lesions in the lung compared with wild-type littermates (Fig. 3, A–C). In a second metastatic model, CT26 or D121 cells were injected beneath the spleen capsule followed by splenectomy, which ultimately results in hepatic metastatic lesions (Xiang et al., 1997). Consistent with the lung model, Yes-deficient mice showed sharply reduced hepatic metastases compared with control animals for either cell line (Fig. 3 D).

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