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Angiopoietin-1 inhibits tumour growth and ascites formation in a murine model of peritoneal carcinomatosis.

Stoeltzing O, Ahmad SA, Liu W, McCarty MF, Parikh AA, Fan F, Reinmuth N, Bucana CD, Ellis LM - Br. J. Cancer (2002)

Bottom Line: Number of peritoneal metastases (P<0.05), tumour volume, (P<0.05), vessel counts (P<0.01), and tumour cell proliferation (P<0.01) were significantly reduced in angiopoietin-1-expressing tumours.Conditioned medium from angiopoietin-1-transfected cells decreased vascular permeability more than did conditioned medium from control cells (P<0.05).Our results suggest that angiopoietin-1 is an important mediator of angiogenesis and vascular permeability and thus could theoretically serve as an anti-neoplastic agent for patients with carcinomatosis from colorectal cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

ABSTRACT
Angiopoietin-1 is an important regulator of endothelial cell survival. Angiopoietin-1 also reduces vascular permeability mediated by vascular endothelial growth factor. The effects of angiopoietin-1 on tumour growth and angiogenesis are controversial. We hypothesised that angiopoietin-1 would decrease tumour growth and ascites formation in peritoneal carcinomatosis. Human colon cancer cells (KM12L4) were transfected with vector (pcDNA) alone (control) or vector containing angiopoietin-1 and injected into the peritoneal cavities of mice. After 30 days, the following parameters were measured: number of peritoneal nodules, ascites volume, and diameter of the largest tumour. Effects of angiopoietin-1 on vascular permeability were investigated using an intradermal Miles assay with conditioned media from transfected cells. Seven of the nine mice in the pcDNA group developed ascites (1.3+/-0.5 ml (mean+/-s.e.m.)), whereas no ascites was detectable in the angiopoietin-1 group (0 out of 10) (P<0.01). Number of peritoneal metastases (P<0.05), tumour volume, (P<0.05), vessel counts (P<0.01), and tumour cell proliferation (P<0.01) were significantly reduced in angiopoietin-1-expressing tumours. Conditioned medium from angiopoietin-1-transfected cells decreased vascular permeability more than did conditioned medium from control cells (P<0.05). Our results suggest that angiopoietin-1 is an important mediator of angiogenesis and vascular permeability and thus could theoretically serve as an anti-neoplastic agent for patients with carcinomatosis from colorectal cancer.

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Effect of Ang-1 overexpression by tumour cells on dermal vascular permeability. Effects on vascular permeability were examined using the Miles in vivo permeability assay. CM from Ang-1- or pcDNA-transfected cells was injected into the dermis of mice. After 20 min, mice were killed, and the areas of dye leakage (as a measure of permeability) were calculated for each injection site. PBS and PBS plus VEGF (10 ng ml−1) served as negative and positive controls, respectively. In contrast to CM of pcDNA-transfected cells, Ang-1-containing CM did not increase plasma leakage, indicating that Ang-1 abrogated permeability effects of tumour cell–derived growth factors in CM (*P<0.05, two-sided Student t-test). Bars: s.e.m.
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fig5: Effect of Ang-1 overexpression by tumour cells on dermal vascular permeability. Effects on vascular permeability were examined using the Miles in vivo permeability assay. CM from Ang-1- or pcDNA-transfected cells was injected into the dermis of mice. After 20 min, mice were killed, and the areas of dye leakage (as a measure of permeability) were calculated for each injection site. PBS and PBS plus VEGF (10 ng ml−1) served as negative and positive controls, respectively. In contrast to CM of pcDNA-transfected cells, Ang-1-containing CM did not increase plasma leakage, indicating that Ang-1 abrogated permeability effects of tumour cell–derived growth factors in CM (*P<0.05, two-sided Student t-test). Bars: s.e.m.

Mentions: To demonstrate whether the observed inhibition of ascites formation was attributable to reduced vascular permeability mediated by Ang-1 and not solely dependent on tumour burden, we used the Miles in vivo permeability assay to determine the direct effect of Ang-1 on vascular permeability. In this assay, effects on vascular permeability were investigated using conditioned media from Ang-1- or pcDNA-transfected KM12L4 cells. Injections with PBS and PBS plus VEGF served as a negative and positive control, respectively. Areas of intradermal dye leakage (a measure of vascular permeability) were significantly smaller at CM-Ang-1 injection sites than at CM-pcDNA injection sites (or PBS-plus-VEGF injection sites, the positive control) (P<0.05) (Figure 5Figure 5


Angiopoietin-1 inhibits tumour growth and ascites formation in a murine model of peritoneal carcinomatosis.

Stoeltzing O, Ahmad SA, Liu W, McCarty MF, Parikh AA, Fan F, Reinmuth N, Bucana CD, Ellis LM - Br. J. Cancer (2002)

Effect of Ang-1 overexpression by tumour cells on dermal vascular permeability. Effects on vascular permeability were examined using the Miles in vivo permeability assay. CM from Ang-1- or pcDNA-transfected cells was injected into the dermis of mice. After 20 min, mice were killed, and the areas of dye leakage (as a measure of permeability) were calculated for each injection site. PBS and PBS plus VEGF (10 ng ml−1) served as negative and positive controls, respectively. In contrast to CM of pcDNA-transfected cells, Ang-1-containing CM did not increase plasma leakage, indicating that Ang-1 abrogated permeability effects of tumour cell–derived growth factors in CM (*P<0.05, two-sided Student t-test). Bars: s.e.m.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2376191&req=5

fig5: Effect of Ang-1 overexpression by tumour cells on dermal vascular permeability. Effects on vascular permeability were examined using the Miles in vivo permeability assay. CM from Ang-1- or pcDNA-transfected cells was injected into the dermis of mice. After 20 min, mice were killed, and the areas of dye leakage (as a measure of permeability) were calculated for each injection site. PBS and PBS plus VEGF (10 ng ml−1) served as negative and positive controls, respectively. In contrast to CM of pcDNA-transfected cells, Ang-1-containing CM did not increase plasma leakage, indicating that Ang-1 abrogated permeability effects of tumour cell–derived growth factors in CM (*P<0.05, two-sided Student t-test). Bars: s.e.m.
Mentions: To demonstrate whether the observed inhibition of ascites formation was attributable to reduced vascular permeability mediated by Ang-1 and not solely dependent on tumour burden, we used the Miles in vivo permeability assay to determine the direct effect of Ang-1 on vascular permeability. In this assay, effects on vascular permeability were investigated using conditioned media from Ang-1- or pcDNA-transfected KM12L4 cells. Injections with PBS and PBS plus VEGF served as a negative and positive control, respectively. Areas of intradermal dye leakage (a measure of vascular permeability) were significantly smaller at CM-Ang-1 injection sites than at CM-pcDNA injection sites (or PBS-plus-VEGF injection sites, the positive control) (P<0.05) (Figure 5Figure 5

Bottom Line: Number of peritoneal metastases (P<0.05), tumour volume, (P<0.05), vessel counts (P<0.01), and tumour cell proliferation (P<0.01) were significantly reduced in angiopoietin-1-expressing tumours.Conditioned medium from angiopoietin-1-transfected cells decreased vascular permeability more than did conditioned medium from control cells (P<0.05).Our results suggest that angiopoietin-1 is an important mediator of angiogenesis and vascular permeability and thus could theoretically serve as an anti-neoplastic agent for patients with carcinomatosis from colorectal cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

ABSTRACT
Angiopoietin-1 is an important regulator of endothelial cell survival. Angiopoietin-1 also reduces vascular permeability mediated by vascular endothelial growth factor. The effects of angiopoietin-1 on tumour growth and angiogenesis are controversial. We hypothesised that angiopoietin-1 would decrease tumour growth and ascites formation in peritoneal carcinomatosis. Human colon cancer cells (KM12L4) were transfected with vector (pcDNA) alone (control) or vector containing angiopoietin-1 and injected into the peritoneal cavities of mice. After 30 days, the following parameters were measured: number of peritoneal nodules, ascites volume, and diameter of the largest tumour. Effects of angiopoietin-1 on vascular permeability were investigated using an intradermal Miles assay with conditioned media from transfected cells. Seven of the nine mice in the pcDNA group developed ascites (1.3+/-0.5 ml (mean+/-s.e.m.)), whereas no ascites was detectable in the angiopoietin-1 group (0 out of 10) (P<0.01). Number of peritoneal metastases (P<0.05), tumour volume, (P<0.05), vessel counts (P<0.01), and tumour cell proliferation (P<0.01) were significantly reduced in angiopoietin-1-expressing tumours. Conditioned medium from angiopoietin-1-transfected cells decreased vascular permeability more than did conditioned medium from control cells (P<0.05). Our results suggest that angiopoietin-1 is an important mediator of angiogenesis and vascular permeability and thus could theoretically serve as an anti-neoplastic agent for patients with carcinomatosis from colorectal cancer.

Show MeSH
Related in: MedlinePlus