Annals of Surgical Oncology

, Volume 8, Issue 3, pp 260–267

Vascular Endothelial Growth Factor and Soft Tissue Sarcomas: Tumor Expression Correlates With Grade

  • Celia Chao
  • Tahseen Al-Saleem
  • John J. Brooks
  • André Rogatko
  • William G. Kraybill
  • Burton Eisenberg
Original Articles


Introduction: Vascular endothelial growth factor (VEGF), an endothelial–specific mitogen overexpressed in various epithelial malignancies is thought to be a potent regulator of angiogenesis. We hypothesized that some soft tissue sarcomas, due to their high propensity for hematogenous metastases (1) would overexpress VEGF, (2) that the degree of expression may represent a significant biologic predictor for disease-specific survival, and (3) that recurrent tumor would express as high or higher VEGF compared with the primary tumor.

Methods: Selected paraffin-embedded tissue of surgical specimens from 79 patients with soft tissue sarcomas, treated between 1989 and 1995 were stained with a rabbit polyclonal anti-VEGF antibody at a concentration of 2 μg/ml. Slides were assessed for VEGF expression as high or low by two investigators blinded to the clinicopathologic data. Twelve patients had VEGF expression of their primary tumors, and their recurrent tumors were compared. The Fishers’ exact test assessed for differences in VEGF expression; survival analyses were performed according to the methods of Kaplan and Meier.

Results: Seventy-eight percent (29 of 37) of patients who died of disease had high VEGF expression. However, VEGF expression was not an independent predictor of either overall or disease-free survival. Tumor grade correlated with VEGF expression significantly. For the low-grade tumors, 7 of 13 expressed low VEGF, whereas for high-grade tumors, 53 of 66 expressed high VEGF (P = .016). Seven of the 12 paired tumor samples expressed identical VEGF immunostaining.

Conclusions: The majority of high-grade soft tissue sarcomas in this study have high intensity VEGF expression. This finding may provide useful information on individual soft tissue sarcomas and offer the basis for therapeutic and biologic targeting in high-risk patients using anti-angiogenesis strategies. However, in our analysis, after accounting for tumor grade, VEGF does not seem to be an independent predictor of clinical outcome.

Key Words:

Vascular endothelial growth factor (VEGF) Soft tissue sarcoma Immunohistochemistry Tumor grade 


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  1. 1.
    Folkman J. Seminars in medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. N Engl J Med 1995; 333: 1757–63.CrossRefPubMedGoogle Scholar
  2. 2.
    Yoshiji H, Gomez DE, Shibuya M, Thorgeirsson UP. Expression of vascular endothelial growth factor, its receptor, and other angiogenic factors in human breast cancer. Cancer Res 1996; 56: 2013–6.PubMedGoogle Scholar
  3. 3.
    Inoue K, Ozeki Y, Suganuma T, Sugiura Y, Tanaka S. Vascular endothelial growth factor expression in primary esophageal squamous cell carcinoma. Cancer 1997; 79: 206–13.CrossRefPubMedGoogle Scholar
  4. 4.
    Maeda K, Chung YS, Ogawa Y, et al. Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer 1996; 77: 858–63.PubMedGoogle Scholar
  5. 5.
    Neitzel LT, Neitzel CD, Magee KL, Malafa MP. Angiogenesis correlates with metastasis in melanoma. Ann Surg Oncol 1999; 6: 70–4.PubMedGoogle Scholar
  6. 6.
    Saito H, Tsujitani S, Kondo A, Ikeguchi M, Maeto M, Kaibara N. Expression of vascular endothelial growth factor correlates with hematogenous recurrence in gastric carcinoma. Surgery 1999; 125: 195–201.PubMedGoogle Scholar
  7. 7.
    Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 1995; 55: 3964–8.PubMedGoogle Scholar
  8. 8.
    Lee AHS, Dublin EA, Bobrow LG, Poulsom R. Invasive lobular and invasive ductal carcinoma of the breast show distinct patterns of vascular endothelial growth factor expression and angiogenesis. J Pathol 1998; 185: 394–401.PubMedGoogle Scholar
  9. 9.
    Salven P, Heikkila P, Anttonen A, Kajanti M, Joensuu H. Vascular endothelial growth factor in squamous cell head and neck carcinoma: expression and prognostic significance. Mod Pathol 1997; 10: 1128–33.PubMedGoogle Scholar
  10. 10.
    Ferrara N, Wuner J, Burton T. Aortic smooth muscle cells express and secrete VEGF. Growth Factors 1991; 5: 141–8.PubMedGoogle Scholar
  11. 11.
    Weidner N, Semple J, Welch W, Folkman J. Tumor angiogenesis and metastasis correlation in invasive breast carcinoma. N Engl J Med 1991; 324: 1–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Lewis CE, Leek R, Harris A, McGee JO. Cytokine regulation of angiogenesis in breast cancer: role of tumor-associated macrophages. J Leukoc Biol 1995; 57: 747–51.PubMedGoogle Scholar
  13. 13.
    Zhang HT, Craft P, Scott PAE, et al. 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; 87: 213–9.PubMedGoogle Scholar
  14. 14.
    Wang G, Dong Z, XuG, et al. The effect of antibody against vascular endothelial growth factor on tumor growth and metastasis. Cancer Res Clin Oncol 1998; 124: 615–20.Google Scholar
  15. 15.
    Angelov L, Salhia B, Roncari L, McMahon G, Guha A. Inhibition of angiogenesis by blocking activation of the vascular endothelial growth factor receptor 2 leads to decreased growth of neurogenic sarcomas. Cancer Res 1999; 59: 5536–41.PubMedGoogle Scholar
  16. 16.
    Kawauchi S, Fukuda T, Tsuneyoshi M. Angiogenesis does not correlate with prognosis or expression of vascular endothelial growth factor in synovial sarcomas. Oncol Rep 1999; 6: 959–64.PubMedGoogle Scholar
  17. 17.
    Linder C, Linder S, Munck-Wikland E, Strander H. Independent expression of serum VEGF and bFGF in patients with carcinoma and sarcoma. Anticancer Res 1998; 18: 2063–8.PubMedGoogle Scholar
  18. 18.
    Salven P, Lymboussaki A, Heikkila P, et al. Vascular endothelial growth factors VEGF-B and VEGF-C are expressed in human tumors. Am J Pathol 1998; 153: 103–8.PubMedGoogle Scholar
  19. 19.
    Graeven U, Andre N, Achilles E, Zornig C, Schmiegel W. Serum levels of vascular endothelial growth factor and basic fibroblast growth factor in patients with soft-tissue sarcoma. J Cancer Res Clin Oncol 1999; 125: 577–81.PubMedGoogle Scholar
  20. 20.
    Saenz NC, Heslin MJ, Adsay V, Lewis JJ, Leung DH, LaQuaglia MP, Brennan MF. Neovascularity and clinical outcome in high grade extremity soft tissue sarcomas. Ann Surg Oncol 1998; 5: 48–53.PubMedGoogle Scholar
  21. 21.
    Kaya M, Wada T, Akatsuka T, et al. Vascular endothelial growth factor expression in untreated osteosarcoma is predictive of pulmonary metastasis and poor prognosis. Clin Cancer Res 2000; 6: 572–7.PubMedGoogle Scholar
  22. 22.
    Emoto M, Iwasaki H, Ishiguro M, et al. Angiogenesis in carcinosarcomas of the uterus: difference in the microvessel density and expression of vascular endothelial growth factor between the epithelial and mesenchymal elements. Hum Pathol 1999; 30: 1232–41.PubMedGoogle Scholar
  23. 23.
    Kim KJ, LiB, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo. Nature 1993; 362: 841–4.CrossRefPubMedGoogle Scholar
  24. 24.
    Goldman CK, Kendall RL, Cabrera G, et al. Paracrine expression of native soluble vascular endothelial growth factor receptor inhibits tumor growth, metastasis, and mortality rate. Proc Natl Acad Sci USA 1998; 95: 8795–800.PubMedGoogle Scholar
  25. 25.
    Tarkkanen M, Huuhtanen R, Virolainen M, et al. Comparison of genetic changes in primary sarcomas and their pulmonary metastases. Genes Chromosomes Cancer 1999; 25: 323–31.PubMedGoogle Scholar

Copyright information

© The Society of Surgical Oncology, Inc. 2001

Authors and Affiliations

  • Celia Chao
    • 1
    • 6
  • Tahseen Al-Saleem
    • 2
  • John J. Brooks
    • 5
  • André Rogatko
    • 3
  • William G. Kraybill
    • 4
  • Burton Eisenberg
    • 1
  1. 1.Department of Surgical OncologyThe Fox Chase Cancer Center, Temple University Medical CenterPhiladelphiaPennsylvania
  2. 2.Department of PathologyThe Fox Chase Cancer Center, Temple University Medical CenterPhiladelphiaPennsylvania
  3. 3.Department of BiostatisticsThe Fox Chase Cancer Center, Temple University Medical CenterPhiladelphiaPennsylvania
  4. 4.Department of Surgical OncologyRoswell Park Cancer InstituteBuffalo
  5. 5.Department of Pathology and Laboratory MedicineRoswell Park Cancer InstituteBuffalo
  6. 6.Department of SurgeryUniversity of LouisvilleLouisvilleKV

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