Reduced tumor growth and angiogenesis in endoglin-haploinsufficient mice.
Endoglin is a transforming growth factor-beta(1) (TGF-beta(1)) accessory receptor which is highly expressed in tumor vessels. To study the role of endoglin in tumor growth and angiogenesis we induced a highly vascularized tumor in mice heterozygous for endoglin (Eng+/-) and in their control littermates (Eng+/+) by injecting 10(6) Lewis lung carcinoma (3LL) cells subcutaneously. Nine days after injection, the tumor was removed and weighed. Capillary density (CD31 immunohistochemistry), hemoglobin content and vascular cell adhesion molecule-1 (VCAM-1) expression were used to assess tumor vascularization. Tumor perfusion rate was measured by laser-Doppler technique. Expression of the hypoxia-inducible factor (HIF), endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) were determined by Western blot analysis. The aerobic metabolism and oxygen dependency were inferred from the measurement of ATP in tumoral tissue. Tumor weight, capillary density, hemoglobin and VCAM-1 were reduced by about 30% in Eng+/- compared to Eng+/+ littermates. The protein levels of eNOS and phosphorylated eNOS were significantly reduced in Eng+/- compared to Eng+/+ mice. HIF expression was slightly reduced whereas VEGF level was slightly increased in Eng+/- compared to Eng+/+. Tumor tissue levels of ATP and ADP were similar in both types of mice. These data demonstrate that endoglin plays a major role in tumor neoangiogenesis.
Düwel
Annette
A
Instituto Reina Sofia de Investigación Nefrológica, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, España.
Eleno
Nélida
N
Jerkic
Mirjana
M
Arevalo
Miguel
M
Bolaños
Juan P
JP
Bernabeu
Carmelo
C
López-Novoa
Jose M
JM
D000818:Animals; D002196:Capillaries / Q000254:growth & development; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000473:pathology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D000071063:Endoglin; D015972:Gene Expression Regulation, Neoplastic; D006239:Haplotypes; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D007668:Kidney / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000098:blood supply* / Q000473:pathology*; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000071063:Endoglin; C502004:Eng protein, mouse; D051793:Hypoxia-Inducible Factor 1; D047908:Intracellular Signaling Peptides and Proteins; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D010100:Oxygen