help button home button The Oncologist
HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pinedo, H.M.
Right arrow Articles by Slamon, D. J.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Pinedo, H.M.
Right arrow Articles by Slamon, D. J.
The Oncologist, Vol. 5, Suppl 1, 1-2, April 2000
© 2000 AlphaMed Press

SUPPLEMENT

INTRODUCTION

Translational Research: The Role of VEGF in Tumor Angiogenesis

H.M. Pinedoa, Dennis J. Slamonb

a Department of Medical Oncology, Free University Hospital, Amsterdam, Netherlands; b Division of Hematology/Oncology, University of California Los Angeles School of Medicine, Los Angeles, California, USA

Correspondence: H.M. Pinedo, M.D., Ph.D., Free University Hospital, Department of Medical Oncology, de Boelelaan 117, 1061 HV Amsterdam, Netherlands. Telephone: 011-31-20-444-43-56; e-mail: pinedo{at}worldaccess.nl

Angiogenesis is defined as the formation of new blood vessels from preexisting vasculature. Preclinical studies have shown the major role of angiogenesis in tumor growth and metastasis formation, and therefore, inhibiting tumor angiogenesis may be a promising therapeutic modality [1, 2]. Paracrine stimuli derived from tumor cells are the main promoters of angiogenesis. Once activated by these stimuli, endothelial cells begin to proliferate and migrate, subsequently resulting in new tube formation and blood flow. This complex process involves numerous biological activities. Vascular endothelial growth factor (VEGF) is one of the most potent and specific angiogenic factors of tumor-induced angiogenesis [3, 4]. Originally identified for its ability to induce vascular permeability and stimulate endothelial cell growth, VEGF is now recognized as a key factor required for growth of tumors [5]. The clinical importance of VEGF for tumor growth is supported by the fact that most tumors produce VEGF and that inhibition of VEGF-induced angiogenesis significantly inhibits tumor growth in vivo [6-8]. In addition to decreasing the number of vessels, antiangiogenic drugs may also decrease the interstitial tumor pressure. This reduction in interstitial pressure may result from the ability of these agents to block VEGF-induced permeability. VEGF expression has been shown to correlate with microvessel density in a number of solid malignancies including carcinomas of the breast, and tissue concentrations of this growth factor appear to be predictive of mortality associated with breast cancer [9, 10]. Similar results have been obtained in studies of solid malignancies in various organs including the lung, prostate, and colon [11-13]. These preclinical and clinical findings support VEGF as a promising target for anticancer therapy.

In patients with cancer, antiangiogenic agents, used alone or combined with chemotherapy, may inhibit tumor growth, reduce metastasis formation, prolong survival, and improve quality of life. Clinicians need to make a major shift in their thinking if the beneficial effects of these novel agents are to be recognized. Appropriate schedules of such combinations need to be developed so that the mechanism of action (i.e., antiangiogenic or cytotoxic) is fully considered. The concern that concomitant administration of antiangiogenic drugs and chemotherapy will impair cytotoxic drug delivery is precluded by evidence from animal studies. Teicher et al. [14-16] clearly demonstrated that combination therapy with angiogenesis inhibitors has synergistic antitumor effects in the Lewis lung carcinoma xenograft model. In these studies, addition of the antiangiogenic agents to the cytotoxic therapies reduced not only the number of lung metastases formed from the primary tumor but also the number of large metastases. These results provide evidence that antiangiogenic therapies can potentiate the efficacy of standard anticancer therapies.

This special issue of The Oncologist presents a diversity of preclinical and clinical studies about anti-VEGF strategies for cancer treatment. McMahon gives an excellent overview of the role of VEGF tyrosine kinase receptors in tumor angiogenesis and the strategies being developed to inhibit this signaling pathway. Subsequently, Ellis presents preclinical data that show the role of VEGF in the growth and metastasis of colon cancer. He also presents evidence that antiangiogenic therapy with VEGF receptor inhibitors SU5416 and SU6668 inhibits the growth of liver metastases. The study by Vajkoczy and coworkers strongly supports the idea that regional differences in Flk-1 activity in vivo may significantly affect tumor susceptibility to compounds that target the VEGF-Flk-1/KDR. Their study evaluated regional VEGF-Flk-1/KDR activities in vivo using SU5416 as measured by intravital fluorescence videomicroscopy. Rosen presents an overview of clinical studies of antiangiogenic therapy. Arastéh and Hannah review evidence that anti-VEGF treatment might also benefit patients with AIDS-related Kaposi's sarcoma. This is followed by an overview by Harris on the role of the von Hippel-Lindau (VHL) tumor-suppressor gene in regulating VEGF expression and the rationale for the use of SU5416 treatment in VHL patients. Gasparini reviews the importance of VEGF tissue levels in treatment planning for breast cancer. Another promising application for anti-VEGF treatment is presented by Verheul and coworkers, who propose SU5416 as a treatment for ascites and pleural effusion formation in patients with advanced-stage cancer. Finally, Carter addresses the challenging question of the selection of strategies for clinical development of angiogenesis inhibitors.


   References
Top
 References
 

  1. Gimbrone MA Jr, Leapman SB, Cotran RS et al. Tumor dormancy in vivo by prevention of neovascularization. J Exp Med 1972;136:261-276.[Abstract]
  2. Graham CH, Rivers J, Kerbel RS et al. Extent of vascularization as a prognostic indicator in thin (<0.76 mm) malignant melanomas. Am J Pathol 1994;145:510-514.[Abstract]
  3. Zhang HT, Craft P, Scott PA 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;87:213-219.[Abstract/Free Full Text]
  4. Claffey KP, Robinson GS. Regulation of VEGF/VPF expression in tumor cells: consequences for tumor growth and metastasis. Cancer Metastasis Rev 1996;15:165-176.[CrossRef][Medline]
  5. Ferrara N, Alitalo K. Clinical applications of angiogenic growth factors and their inhibitors. Nat Med 1999;5:1359-1364.[CrossRef][Medline]
  6. Kim KJ, Li B, Winer J et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993;362:841-844.[CrossRef][Medline]
  7. Millauer B, Shawver LK, Plate KH et al. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 1994;367:576-579.[CrossRef][Medline]
  8. Saleh M, Stacker SA, Wilks AF. Inhibition of growth of C6 glioma cells in vivo by expression of antisense vascular endothelial growth factor sequence. Cancer Res 1996;56:393-401.[Abstract/Free Full Text]
  9. Linderholm B, Tavelin B, Grankvist K et al. Vascular endothelial growth factor is of high prognostic value in node-negative breast carcinoma. J Clin Oncol 1998;16:3121-3128.[Abstract/Free Full Text]
  10. Linderholm B, Tavelin B, Grankvist K et al. Does vascular endothelial growth factor (VEGF) predict local relapse and survival in radiotherapy-treated node-negative breast cancer? Br J Cancer 1999;81:727-732.[CrossRef][Medline]
  11. Takahashi Y, Kitadai Y, Bucana CD et al. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 1995;55:3964-3968.[Abstract/Free Full Text]
  12. Weidner N, Carroll PR, Flax J et al. Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 1993;143:401-409.[Abstract]
  13. Mattern J, Koomagi R, Volm M. Association of vascular endothelial growth factor expression with intratumoral microvessel density and tumour cell proliferation in human epidermoid lung carcinoma. Br J Cancer 1996;73:931-934.[Medline]
  14. Teicher BA, Sotomayor EA, Huang ZD. Antiangiogenic agents potentiate cytotoxic cancer therapies against primary and metastatic disease. Cancer Res 1992;52:6702-6704.[Abstract/Free Full Text]
  15. Teicher BA, Holden SA, Ara G et al. Response of the FSaII fibrosarcoma to antiangiogenic modulators plus cytotoxic agents. Anticancer Res 1993;13:2101-2106.[Medline]
  16. Teicher BA, Holden SA, Ara G et al. Potentiation of cytotoxic cancer therapies by TNP-470 alone and with other anti-angiogenic agents. Int J Cancer 1994;57:920-925.[Medline]




This Article
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pinedo, H.M.
Right arrow Articles by Slamon, D. J.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Pinedo, H.M.
Right arrow Articles by Slamon, D. J.

HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
THE ONCOLOGIST STEM CELLS CME ALPHAMED PRESS JOURNALS