Abstract
Previous studies have shown that the prognosis of patients who have tumours with high microvessel density (MVD) is worse than that of patients who have a lower density in a variety of cancers. In this study, we investigated the clinical relevance of neovascularity assessed by MVD and the concentration of vascular endothelial growth factor (VEGF) in the tumour tissue of patients with soft tissue sarcoma in comparison with major clinicohistologic parameters by univariate and multivariate analysis. In 115 patients with soft tissue sarcoma, MVD was measured by counting vessels stained with factor VIII antibody. The concentration of VEGF in the tumour tissue was determined by enzyme-linked immunosorbent assay. These parameters were then compared with disease outcome. The concentration of VEGF in the tumour tissue, but not MVD, was found to be correlated with disease outcome in patients with soft tissue, sarcoma. VEGF concentration in the tumour tissue showed a relationship with the clinical stage and histologic grade of the tumour. There was no significant difference in the levels of tissue VEGF concentration and MVD among soft tissue sarcomas classified according to histologic type. The level of tissue VEGF concentration in patients who had subsequent local recurrence and metastasis were significantly higher than the respective values in patients who did not have such disease outcome. No significant correlation existed between MVD and the concentration of VEGF in the tumour tissue. Univariate analysis showed that a high tissue VEGF concentration was associated with poor overall survival of the patient and a greater probability that local recurrence and metastasis had occurred. Multivariate analysis revealed that the tissue concentration of VEGF is an independent prognostic factor for the disease outcome of patients with soft tissue sarcoma. VEGF concentration in the tumour tissue, but not MVD, is an additional prognostic parameter for disease outcome in patients with soft tissue sarcoma, regardless of histologic type. © 2001 Cancer Research Campaign http://www.bjcancer.com
Keywords: microvessel density, vascular endothelial growth factor, overall survival, tumour recurrence, metastasis, soft tissuearcoma
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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]
- Boocock C. A., Charnock-Jones D. S., Sharkey A. M., McLaren J., Barker P. J., Wright K. A., Twentyman P. R., Smith S. K. Expression of vascular endothelial growth factor and its receptors flt and KDR in ovarian carcinoma. J Natl Cancer Inst. 1995 Apr 5;87(7):506–516. doi: 10.1093/jnci/87.7.506. [DOI] [PubMed] [Google Scholar]
- Borgström P., Hillan K. J., Sriramarao P., Ferrara N. Complete inhibition of angiogenesis and growth of microtumors by anti-vascular endothelial growth factor neutralizing antibody: novel concepts of angiostatic therapy from intravital videomicroscopy. Cancer Res. 1996 Sep 1;56(17):4032–4039. [PubMed] [Google Scholar]
- Brawer M. K. Quantitative microvessel density. A staging and prognostic marker for human prostatic carcinoma. Cancer. 1996 Jul 15;78(2):345–349. doi: 10.1002/(SICI)1097-0142(19960715)78:2<345::AID-CNCR25>3.0.CO;2-V. [DOI] [PubMed] [Google Scholar]
- Claffey K. P., Brown L. F., del Aguila L. F., Tognazzi K., Yeo K. T., Manseau E. J., Dvorak H. F. Expression of vascular permeability factor/vascular endothelial growth factor by melanoma cells increases tumor growth, angiogenesis, and experimental metastasis. Cancer Res. 1996 Jan 1;56(1):172–181. [PubMed] [Google Scholar]
- Coindre J. M., Terrier P., Bui N. B., Bonichon F., Collin F., Le Doussal V., Mandard A. M., Vilain M. O., Jacquemier J., Duplay H. Prognostic factors in adult patients with locally controlled soft tissue sarcoma. A study of 546 patients from the French Federation of Cancer Centers Sarcoma Group. J Clin Oncol. 1996 Mar;14(3):869–877. doi: 10.1200/JCO.1996.14.3.869. [DOI] [PubMed] [Google Scholar]
- Folkman J. How is blood vessel growth regulated in normal and neoplastic tissue? G.H.A. Clowes memorial Award lecture. Cancer Res. 1986 Feb;46(2):467–473. [PubMed] [Google Scholar]
- Folkman J., Watson K., Ingber D., Hanahan D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature. 1989 May 4;339(6219):58–61. doi: 10.1038/339058a0. [DOI] [PubMed] [Google Scholar]
- Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 1990 Jan 3;82(1):4–6. doi: 10.1093/jnci/82.1.4. [DOI] [PubMed] [Google Scholar]
- Gasparini G., Bonoldi E., Viale G., Verderio P., Boracchi P., Panizzoni G. A., Radaelli U., Di Bacco A., Guglielmi R. B., Bevilacqua P. Prognostic and predictive value of tumour angiogenesis in ovarian carcinomas. Int J Cancer. 1996 Jun 21;69(3):205–211. doi: 10.1002/(SICI)1097-0215(19960621)69:3<205::AID-IJC10>3.0.CO;2-6. [DOI] [PubMed] [Google Scholar]
- Gaynor J. J., Tan C. C., Casper E. S., Collin C. F., Friedrich C., Shiu M., Hajdu S. I., Brennan M. F. Refinement of clinicopathologic staging for localized soft tissue sarcoma of the extremity: a study of 423 adults. J Clin Oncol. 1992 Aug;10(8):1317–1329. doi: 10.1200/JCO.1992.10.8.1317. [DOI] [PubMed] [Google Scholar]
- Gimbrone M. A., Jr, Cotran R. S., Leapman S. B., Folkman J. Tumor growth and neovascularization: an experimental model using the rabbit cornea. J Natl Cancer Inst. 1974 Feb;52(2):413–427. doi: 10.1093/jnci/52.2.413. [DOI] [PubMed] [Google Scholar]
- Gimbrone M. A., Jr, Leapman S. B., Cotran R. S., Folkman J. Tumor dormancy in vivo by prevention of neovascularization. J Exp Med. 1972 Aug 1;136(2):261–276. doi: 10.1084/jem.136.2.261. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liotta L. A., Kleinerman J., Saidel G. M. Quantitative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. Cancer Res. 1974 May;34(5):997–1004. [PubMed] [Google Scholar]
- Liotta L. A., Steeg P. S., Stetler-Stevenson W. G. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell. 1991 Jan 25;64(2):327–336. doi: 10.1016/0092-8674(91)90642-c. [DOI] [PubMed] [Google Scholar]
- Maeda K., Chung Y. S., Ogawa Y., Takatsuka S., Kang S. M., Ogawa M., Sawada T., Sowa M. Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer. 1996 Mar 1;77(5):858–863. doi: 10.1002/(sici)1097-0142(19960301)77:5<858::aid-cncr8>3.0.co;2-a. [DOI] [PubMed] [Google Scholar]
- Maeda K., Chung Y. S., Takatsuka S., Ogawa Y., Sawada T., Yamashita Y., Onoda N., Kato Y., Nitta A., Arimoto Y. Tumor angiogenesis as a predictor of recurrence in gastric carcinoma. J Clin Oncol. 1995 Feb;13(2):477–481. doi: 10.1200/JCO.1995.13.2.477. [DOI] [PubMed] [Google Scholar]
- Mandard A. M., Petiot J. F., Marnay J., Mandard J. C., Chasle J., de Ranieri E., Dupin P., Herlin P., de Ranieri J., Tanguy A. Prognostic factors in soft tissue sarcomas. A multivariate analysis of 109 cases. Cancer. 1989 Apr 1;63(7):1437–1451. doi: 10.1002/1097-0142(19890401)63:7<1437::aid-cncr2820630735>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
- Miller J. W., Adamis A. P., Shima D. T., D'Amore P. A., Moulton R. S., O'Reilly M. S., Folkman J., Dvorak H. F., Brown L. F., Berse B. Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. Am J Pathol. 1994 Sep;145(3):574–584. [PMC free article] [PubMed] [Google Scholar]
- Presta L. G., Chen H., O'Connor S. J., Chisholm V., Meng Y. G., Krummen L., Winkler M., Ferrara N. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 1997 Oct 15;57(20):4593–4599. [PubMed] [Google Scholar]
- Takahashi Y., Cleary K. R., Mai M., Kitadai Y., Bucana C. D., Ellis L. M. Significance of vessel count and vascular endothelial growth factor and its receptor (KDR) in intestinal-type gastric cancer. Clin Cancer Res. 1996 Oct;2(10):1679–1684. [PubMed] [Google Scholar]
- Takahashi Y., Kitadai Y., Bucana C. D., Cleary K. R., Ellis L. M. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res. 1995 Sep 15;55(18):3964–3968. [PubMed] [Google Scholar]
- Takano S., Yoshii Y., Kondo S., Suzuki H., Maruno T., Shirai S., Nose T. Concentration of vascular endothelial growth factor in the serum and tumor tissue of brain tumor patients. Cancer Res. 1996 May 1;56(9):2185–2190. [PubMed] [Google Scholar]
- Takebayashi Y., Aklyama S., Yamada K., Akiba S., Aikou T. Angiogenesis as an unfavorable prognostic factor in human colorectal carcinoma. Cancer. 1996 Jul 15;78(2):226–231. doi: 10.1002/(SICI)1097-0142(19960715)78:2<226::AID-CNCR6>3.0.CO;2-J. [DOI] [PubMed] [Google Scholar]
- Yamazaki K., Abe S., Takekawa H., Sukoh N., Watanabe N., Ogura S., Nakajima I., Isobe H., Inoue K., Kawakami Y. Tumor angiogenesis in human lung adenocarcinoma. Cancer. 1994 Oct 15;74(8):2245–2250. doi: 10.1002/1097-0142(19941015)74:8<2245::aid-cncr2820740807>3.0.co;2-x. [DOI] [PubMed] [Google Scholar]
- Yeo K. T., Wang H. H., Nagy J. A., Sioussat T. M., Ledbetter S. R., Hoogewerf A. J., Zhou Y., Masse E. M., Senger D. R., Dvorak H. F. Vascular permeability factor (vascular endothelial growth factor) in guinea pig and human tumor and inflammatory effusions. Cancer Res. 1993 Jun 15;53(12):2912–2918. [PubMed] [Google Scholar]
- Zhang H. T., Craft P., Scott P. A., Ziche M., Weich H. A., Harris A. L., Bicknell R. Enhancement of tumor growth and vascular density by transfection of vascular endothelial cell growth factor into MCF-7 human breast carcinoma cells. J Natl Cancer Inst. 1995 Feb 1;87(3):213–219. doi: 10.1093/jnci/87.3.213. [DOI] [PubMed] [Google Scholar]