This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, L. Articles by Lev, D. Search for Related Content PubMed PubMed Citation Articles by Zhang, L. Articles by Lev, D.

Vascular Endothelial Growth Factor Overexpression by Soft Tissue Sarcoma Cells: Implications for Tumor Growth, Metastasis, and Chemoresistance

Departments of ¹ Surgical Oncology and ² Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas and ³ Department of Immunology, ImClone Systems, Inc., New York, New York

Requests for reprints: Dina Lev, Department of Cancer Biology, Unit 173, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-1637; Fax: 713-792-0722; E-mail: dlev{at}mdanderson.org.

To better elucidate the role of vascular endothelial growth factor (VEGF)₁₆₅ in soft tissue sarcoma (STS) growth, metastasis, and chemoresistance, we generated stably transfected human STS cell lines with VEGF₁₆₅ to study the effect of VEGF₁₆₅ on STS cells in vitro and the effect of culture medium from these cells on human umbilical vascular endothelial cells. Severe combined immunodeficient mice bearing xenografts of transfected cell lines were used to assess the effect of VEGF overexpression and the effect of VEGF receptor (VEGFR) 2 inhibition on STS growth, metastasis, and response to doxorubicin. VEGF₁₆₅-transfected xenografts formed highly vascular tumors with shorter latency, accelerated growth, enhanced chemoresistance, and increased incidence of pulmonary metastases. Blockade of VEGFR2 signaling using DC101 anti-VEGFR2 monoclonal antibody enhanced doxorubicin chemoresponse; this combined biochemotherapy inhibited tumor growth and decreased pulmonary metastases without overt toxicity. Combined therapy reduced microvessel counts while increasing vessel maturation index. VEGF overexpression did not affect on the sarcoma cells per se; however, conditioned medium from VEGF transfectants caused increased endothelial cell proliferation, migration, and chemoresistance. Addition of DC101 induced endothelial cell sensitivity to doxorubicin and suppressed the activity of matrix metalloproteinases secreted by endothelial cells. We therefore conclude that VEGF is a critical determinant of STS growth and metastasis and that STS chemoresistance, in our model, is a process induced by the interplay between STS cells and tumor-associated endothelial cells. STS growth and metastasis can be interrupted by combined low-dose doxorubicin and anti-VEGFR2, a strategy that attacks STS-associated endothelial cells. In the future, such therapeutic approaches may be useful in treating STS before the development of clinically apparent metastases. (Cancer Res 2006; 66(17): 8770-7)

This article has been cited by other articles:

				S. Sleijfer, W. T.A. van der Graaf, and J.-Y. Blay Angiogenesis Inhibition in Non-GIST Soft Tissue Sarcomas Oncologist, November 1, 2008; 13(11): 1193 - 1200. [Abstract] [Full Text] [PDF]

				W. Ren, B. Korchin, G. Lahat, C. Wei, S. Bolshakov, T. Nguyen, W. Merritt, A. Dicker, A. Lazar, A. Sood, et al. Combined Vascular Endothelial Growth Factor Receptor/Epidermal Growth Factor Receptor Blockade with Chemotherapy for Treatment of Local, Uterine, and Metastatic Soft Tissue Sarcoma Clin. Cancer Res., September 1, 2008; 14(17): 5466 - 5475. [Abstract] [Full Text] [PDF]

				Q.-S. Zhu, W. Ren, B. Korchin, G. Lahat, A. Dicker, Y. Lu, G. Mills, R. E. Pollock, and D. Lev Soft Tissue Sarcoma Cells Are Highly Sensitive to AKT Blockade: A Role for p53-Independent Up-regulation of GADD45{alpha} Cancer Res., April 15, 2008; 68(8): 2895 - 2903. [Abstract] [Full Text] [PDF]

				M. Sumitomo, F. Koizumi, T. Asano, A. Horiguchi, K. Ito, T. Asano, T. Kakizoe, M. Hayakawa, and Y. Matsumura Novel SN-38-Incorporated Polymeric Micelle, NK012, Strongly Suppresses Renal Cancer Progression Cancer Res., March 15, 2008; 68(6): 1631 - 1635. [Abstract] [Full Text] [PDF]

				M. Tascilar, W. J. Loos, C. Seynaeve, J. Verweij, and S. Sleijfer The Pharmacologic Basis of Ifosfamide Use in Adult Patients with Advanced Soft Tissue Sarcomas Oncologist, November 1, 2007; 12(11): 1351 - 1360. [Abstract] [Full Text] [PDF]

				S. Sleijfer, E. Wiemer, C. Seynaeve, and J. Verweij Improved Insight into Resistance Mechanisms to Imatinib in Gastrointestinal Stromal Tumors: A Basis for Novel Approaches and Individualization of Treatment Oncologist, June 1, 2007; 12(6): 719 - 726. [Abstract] [Full Text] [PDF]