Abstract
Vascular permeability factor (VPF), also known as vascular endothelial growth factor, is a secreted protein implicated in tumor-associated microvascular hyperpermeability and angiogenesis. Tumor cells in 11 of 12 renal cell carcinomas expressed high levels of VPF messenger RNA (mRNA) by in situ hybridization, the only exception being a case of the relatively avascular papillary variant. Expression was further accentuated adjacent to areas of necrosis. Both tumor cells and endothelial cells in small vessels adjacent to tumor stained strongly for VPF protein by immunohistochemistry. Endothelial cells did not express detectable VPF mRNA, but did express high levels of mRNA for the VPF receptors flt-1 and KDR indicating that the endothelial cell staining likely reflects binding of VPF secreted by adjacent tumor cells. Three transitional cell carcinomas also labeled strongly for VPF mRNA. These data suggest an important role for VPF in the vascular biology of these two common human malignancies.
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- Berkman R. A., Merrill M. J., Reinhold W. C., Monacci W. T., Saxena A., Clark W. C., Robertson J. T., Ali I. U., Oldfield E. H. Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms. J Clin Invest. 1993 Jan;91(1):153–159. doi: 10.1172/JCI116165. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Berse B., Brown L. F., Van de Water L., Dvorak H. F., Senger D. R. Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol Cell. 1992 Feb;3(2):211–220. doi: 10.1091/mbc.3.2.211. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Boczko S., Fromowitz F. B., Bard R. H. Papillary adenocarcinoma of kidney: a new perspective. Urology. 1979 Nov;14(5):491–495. doi: 10.1016/0090-4295(79)90182-1. [DOI] [PubMed] [Google Scholar]
- Brock T. A., Dvorak H. F., Senger D. R. Tumor-secreted vascular permeability factor increases cytosolic Ca2+ and von Willebrand factor release in human endothelial cells. Am J Pathol. 1991 Jan;138(1):213–221. [PMC free article] [PubMed] [Google Scholar]
- Brown L. F., Berse B., Tognazzi K., Manseau E. J., Van de Water L., Senger D. R., Dvorak H. F., Rosen S. Vascular permeability factor mRNA and protein expression in human kidney. Kidney Int. 1992 Dec;42(6):1457–1461. doi: 10.1038/ki.1992.441. [DOI] [PubMed] [Google Scholar]
- Brown L. F., Lanir N., McDonagh J., Tognazzi K., Dvorak A. M., Dvorak H. F. Fibroblast migration in fibrin gel matrices. Am J Pathol. 1993 Jan;142(1):273–283. [PMC free article] [PubMed] [Google Scholar]
- Brown L. F., Yeo K. T., Berse B., Yeo T. K., Senger D. R., Dvorak H. F., van de Water L. Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing. J Exp Med. 1992 Nov 1;176(5):1375–1379. doi: 10.1084/jem.176.5.1375. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Clauss M., Gerlach M., Gerlach H., Brett J., Wang F., Familletti P. C., Pan Y. C., Olander J. V., Connolly D. T., Stern D. Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration. J Exp Med. 1990 Dec 1;172(6):1535–1545. doi: 10.1084/jem.172.6.1535. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Conn G., Bayne M. L., Soderman D. D., Kwok P. W., Sullivan K. A., Palisi T. M., Hope D. A., Thomas K. A. Amino acid and cDNA sequences of a vascular endothelial cell mitogen that is homologous to platelet-derived growth factor. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2628–2632. doi: 10.1073/pnas.87.7.2628. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Connolly D. T., Heuvelman D. M., Nelson R., Olander J. V., Eppley B. L., Delfino J. J., Siegel N. R., Leimgruber R. M., Feder J. Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest. 1989 Nov;84(5):1470–1478. doi: 10.1172/JCI114322. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Connolly D. T., Olander J. V., Heuvelman D., Nelson R., Monsell R., Siegel N., Haymore B. L., Leimgruber R., Feder J. Human vascular permeability factor. Isolation from U937 cells. J Biol Chem. 1989 Nov 25;264(33):20017–20024. [PubMed] [Google Scholar]
- Dvorak H. F., Harvey V. S., Estrella P., Brown L. F., McDonagh J., Dvorak A. M. Fibrin containing gels induce angiogenesis. Implications for tumor stroma generation and wound healing. Lab Invest. 1987 Dec;57(6):673–686. [PubMed] [Google Scholar]
- Dvorak H. F., Orenstein N. S., Carvalho A. C., Churchill W. H., Dvorak A. M., Galli S. J., Feder J., Bitzer A. M., Rypysc J., Giovinco P. Induction of a fibrin-gel investment: an early event in line 10 hepatocarcinoma growth mediated by tumor-secreted products. J Immunol. 1979 Jan;122(1):166–174. [PubMed] [Google Scholar]
- Dvorak H. F., Sioussat T. M., Brown L. F., Berse B., Nagy J. A., Sotrel A., Manseau E. J., Van de Water L., Senger D. R. Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vessels. J Exp Med. 1991 Nov 1;174(5):1275–1278. doi: 10.1084/jem.174.5.1275. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ferrara N., Henzel W. J. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 1989 Jun 15;161(2):851–858. doi: 10.1016/0006-291x(89)92678-8. [DOI] [PubMed] [Google Scholar]
- Folkman J., Shing Y. Angiogenesis. J Biol Chem. 1992 Jun 5;267(16):10931–10934. [PubMed] [Google Scholar]
- Gospodarowicz D., Abraham J. A., Schilling J. Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary-derived folliculo stellate cells. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7311–7315. doi: 10.1073/pnas.86.19.7311. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Houck K. A., Ferrara N., Winer J., Cachianes G., Li B., Leung D. W. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol. 1991 Dec;5(12):1806–1814. doi: 10.1210/mend-5-12-1806. [DOI] [PubMed] [Google Scholar]
- Houck K. A., Leung D. W., Rowland A. M., Winer J., Ferrara N. Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem. 1992 Dec 25;267(36):26031–26037. [PubMed] [Google Scholar]
- Keck P. J., Hauser S. D., Krivi G., Sanzo K., Warren T., Feder J., Connolly D. T. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989 Dec 8;246(4935):1309–1312. doi: 10.1126/science.2479987. [DOI] [PubMed] [Google Scholar]
- Kim K. J., Li B., Winer J., Armanini M., Gillett N., Phillips H. S., Ferrara N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993 Apr 29;362(6423):841–844. doi: 10.1038/362841a0. [DOI] [PubMed] [Google Scholar]
- Lanir N., Ciano P. S., Van de Water L., McDonagh J., Dvorak A. M., Dvorak H. F. Macrophage migration in fibrin gel matrices. II. Effects of clotting factor XIII, fibronectin, and glycosaminoglycan content on cell migration. J Immunol. 1988 Apr 1;140(7):2340–2349. [PubMed] [Google Scholar]
- Leung D. W., Cachianes G., Kuang W. J., Goeddel D. V., Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989 Dec 8;246(4935):1306–1309. doi: 10.1126/science.2479986. [DOI] [PubMed] [Google Scholar]
- Mancilla-Jimenez R., Stanley R. J., Blath R. A. Papillary renal cell carcinoma: a clinical, radiologic, and pathologic study of 34 cases. Cancer. 1976 Dec;38(6):2469–2480. doi: 10.1002/1097-0142(197612)38:6<2469::aid-cncr2820380636>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
- Mosher D. F. Cross-linking of plasma and cellular fibronectin by plasma transglutaminase. Ann N Y Acad Sci. 1978 Jun 20;312:38–42. doi: 10.1111/j.1749-6632.1978.tb16791.x. [DOI] [PubMed] [Google Scholar]
- Myoken Y., Kayada Y., Okamoto T., Kan M., Sato G. H., Sato J. D. Vascular endothelial cell growth factor (VEGF) produced by A-431 human epidermoid carcinoma cells and identification of VEGF membrane binding sites. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5819–5823. doi: 10.1073/pnas.88.13.5819. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pepper M. S., Ferrara N., Orci L., Montesano R. Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor-1 in microvascular endothelial cells. Biochem Biophys Res Commun. 1991 Dec 16;181(2):902–906. doi: 10.1016/0006-291x(91)91276-i. [DOI] [PubMed] [Google Scholar]
- Plate K. H., Breier G., Weich H. A., Risau W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature. 1992 Oct 29;359(6398):845–848. doi: 10.1038/359845a0. [DOI] [PubMed] [Google Scholar]
- Roberts W. G., Hasan T. Tumor-secreted vascular permeability factor/vascular endothelial growth factor influences photosensitizer uptake. Cancer Res. 1993 Jan 1;53(1):153–157. [PubMed] [Google Scholar]
- Senger D. R., Connolly D. T., Van de Water L., Feder J., Dvorak H. F. Purification and NH2-terminal amino acid sequence of guinea pig tumor-secreted vascular permeability factor. Cancer Res. 1990 Mar 15;50(6):1774–1778. [PubMed] [Google Scholar]
- Senger D. R., Galli S. J., Dvorak A. M., Perruzzi C. A., Harvey V. S., Dvorak H. F. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983 Feb 25;219(4587):983–985. doi: 10.1126/science.6823562. [DOI] [PubMed] [Google Scholar]
- Senger D. R., Perruzzi C. A., Feder J., Dvorak H. F. A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res. 1986 Nov;46(11):5629–5632. [PubMed] [Google Scholar]
- Shweiki D., Itin A., Soffer D., Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992 Oct 29;359(6398):843–845. doi: 10.1038/359843a0. [DOI] [PubMed] [Google Scholar]
- Sioussat T. M., Dvorak H. F., Brock T. A., Senger D. R. Inhibition of vascular permeability factor (vascular endothelial growth factor) with antipeptide antibodies. Arch Biochem Biophys. 1993 Feb 15;301(1):15–20. doi: 10.1006/abbi.1993.1109. [DOI] [PubMed] [Google Scholar]
- Terman B. I., Carrion M. E., Kovacs E., Rasmussen B. A., Eddy R. L., Shows T. B. Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene. 1991 Sep;6(9):1677–1683. [PubMed] [Google Scholar]
- Terman B. I., Dougher-Vermazen M., Carrion M. E., Dimitrov D., Armellino D. C., Gospodarowicz D., Böhlen P. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun. 1992 Sep 30;187(3):1579–1586. doi: 10.1016/0006-291x(92)90483-2. [DOI] [PubMed] [Google Scholar]
- Tischer E., Mitchell R., Hartman T., Silva M., Gospodarowicz D., Fiddes J. C., Abraham J. A. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem. 1991 Jun 25;266(18):11947–11954. [PubMed] [Google Scholar]
- Unemori E. N., Ferrara N., Bauer E. A., Amento E. P. Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. J Cell Physiol. 1992 Dec;153(3):557–562. doi: 10.1002/jcp.1041530317. [DOI] [PubMed] [Google Scholar]
- de Vries C., Escobedo J. A., Ueno H., Houck K., Ferrara N., Williams L. T. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science. 1992 Feb 21;255(5047):989–991. doi: 10.1126/science.1312256. [DOI] [PubMed] [Google Scholar]