DOI: 10.1073/pnas.93.25.14765. Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody

Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody

10.1073/pnas.93.25.14765

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

The hyperpermeability of tumor vessels to macromolecules, compared with normal vessels, is presumably due to vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) released by neoplastic and/or host cells. In addition, VEGF/VPF is a potent angiogenic factor. Removal of this growth factor may reduce the permeability and inhibit tumor angiogenesis. To test these hypotheses, we transplanted a human glioblastoma (U87), a human colon adenocarcinoma (LS174T), and a human melanoma (P-MEL) into two locations in immunodeficient mice: the cranial window and the dorsal skinfold chamber. The mice bearing vascularized tumors were treated with a bolus (0.2 ml) of either a neutralizing antibody (A4.6.1) (492 μg/ml) against VEGF/VPF or PBS (control). We found that tumor vascular permeability to albumin in antibody-treated groups was lower than in the matched controls and that the effect of the antibody was time-dependent and influenced by the mode of injection. Tumor vascular permeability did not respond to i.p. injection of the antibody until 4 days posttreatment. However, the permeability was reduced within 6 h after i.v. injection of the same amount of antibody. In addition to the reduction in vascular permeability, the tumor vessels became smaller in diameter and less tortuous after antibody injections and eventually disappeared from the surface after four consecutive treatments in U87 tumors. These results demonstrate that tumor vascular permeability can be reduced by neutralization of endogenous VEGF/VPF and suggest that angiogenesis and the maintenance of integrity of tumor vessels require the presence of VEGF/VPF in the tissue microenvironment. The latter finding reveals a new mechanism of tumor vessel regression—i.e., blocking the interactions between VEGF/VPF and endothelial cells or inhibiting VEGF/VPF synthesis in solid tumors causes dramatic reduction in vessel diameter, which may block the passage of blood elements and thus lead to vascular regression.

Bibliography

Yuan, F., Chen, Y., Dellian, M., Safabakhsh, N., Ferrara, N., & Jain, R. K. (1996). Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factorâantibody. Proceedings of the National Academy of Sciences, 93(25), 14765â14770.

Authors 6

Fan Yuan (first)
Yi Chen (additional)
Marc Dellian (additional)
Nina Safabakhsh (additional)
Napoleone Ferrara (additional)
Rakesh K. Jain (additional)

References 34 Referenced 550

10.1016/0026-2862(86)90018-X
10.1007/BF00047468
10.1006/mvre.1993.1024
F Yuan, H A Salehi, Y Boucher, U S Vasthare, R F Tuma, R K Jain Cancer Res 54, 4564–4568 (1994). / Cancer Res by Yuan F (1994)
10.1006/mvre.1993.1049
H F Dvorak, L F Brown, M Detmar, A M Dvorak Am J Pathol 146, 1029–1039 (1995). / Am J Pathol by Dvorak H F (1995)
10.1111/j.1749-6632.1995.tb17435.x
W G Roberts, T Hasan Cancer Res 53, 153–157 (1993). / Cancer Res by Roberts W G (1993)
J Rak, Y Mitsuhashi, L Bayko, J Filmus, S Shirasawa, T Sasazuki, R S Kerbel Cancer Res 55, 4575–4580 (1995). / Cancer Res by Rak J (1995)
A J G Pötgens, M C van Altena, N H Lubsen, D J Ruiter, R M W de Waal Am J Pathol 148, 1203–1217 (1996). / Am J Pathol by Pötgens A J G (1996)
10.3109/08977199209023937
D R Senger, C A Perruzzi, J Feder, H F Dvorak Cancer Res 46, 5629–5632 (1986). / Cancer Res by Senger D R (1986)
10.1242/jcs.108.6.2369
D R Senger Am J Pathol 149, 1–8 (1996). / Am J Pathol by Senger D R (1996)
10.1038/380435a0
10.1038/380439a0
M Asano, A Yukita, T Matsumoto, S Kondo, H Suzuki Cancer Res 55, 5296–5301 (1995). / Cancer Res by Asano M (1995)
10.1038/362841a0
10.1172/JCI117857
O Melnyk, M A Shuman, K J Kim Cancer Res 56, 921–924 (1996). / Cancer Res by Melnyk O (1996)
M Leunig, F Yuan, M D Menger, Y Boucher, A E Goetz, K Messmer, R K Jain Cancer Res 52, 6553–6560 (1992). / Cancer Res by Leunig M (1992)
B Endrich, H S Reinhold, J F Gross, M Intaglietta J Natl Cancer Inst 62, 387–395 (1979). / J Natl Cancer Inst by Endrich B (1979)
10.1148/125.1.231
A W Gramza, J M Lucas, R E Mountain, D E Schuller, J C Lang BioTechniques 18, 228–229 (1995). / BioTechniques by Gramza A W (1995)
10.1083/jcb.118.6.1511
M Dellian, B P Witwer, H A Salehi, F Yuan, R K Jain Am J Pathol 149, 59–72 (1996). / Am J Pathol by Dellian M (1996)
10.1038/nm1095-1024
10.1038/nm0295-149
H G Augustin, K Braun, I Telemenakis, U Modlich, W Kuhn Am J Pathol 147, 339–351 (1995). / Am J Pathol by Augustin H G (1995)
R K Jain Cancer Res 48, 2641–2658 (1988). / Cancer Res by Jain R K (1988)
10.1038/nm0996-992
10.1007/BF00437472
10.1146/annurev.ph.57.030195.004143
Y Takahashi, Y Kitadai, C D Bucana, K R Cleary, L M Ellis Cancer Res 55, 3964–3968 (1995). / Cancer Res by Takahashi Y (1995)

Dates

Type	When
Created	23 years ago (July 26, 2002, 10:40 a.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 2:32 p.m.)
Indexed	2 weeks, 3 days ago (Aug. 6, 2025, 9:21 a.m.)
Issued	28 years, 8 months ago (Dec. 10, 1996)
Published	28 years, 8 months ago (Dec. 10, 1996)
Published Online	28 years, 8 months ago (Dec. 10, 1996)
Published Print	28 years, 8 months ago (Dec. 10, 1996)

Funders 0

None

BibTeX

@article{Yuan_1996, title={Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody}, volume={93}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.93.25.14765}, DOI={10.1073/pnas.93.25.14765}, number={25}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Yuan, Fan and Chen, Yi and Dellian, Marc and Safabakhsh, Nina and Ferrara, Napoleone and Jain, Rakesh K.}, year={1996}, month=dec, pages={14765–14770} }

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