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

Abstract

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 VEGF 165 to study the effect of VEGF 165 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. VEGF 165 -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): 8770-8)

Chemokine receptor CXCR4 expression is correlated with VEGF expression and poor survival in soft‐tissue sarcoma

“…[28][29][30] In a leiomyosarcoma cell line, critical roles of VEGF in growth and metastasis have been demonstrated. 31 In a large series of soft-tissue sarcomas, Yudoh et al 28 demonstrated that higher VEGF levels in tumor tissue were correlated with higher tumor stage and grade, increased risk of local and distant tumor recurrence, and poor overall survival, whereas Chao et al 32 failed to demonstrate any relationship between VEGF expression and patients' outcome. In our results, higher VEGF mRNA expression was also correlated with poor prognosis in the group of MNRCT.…”

Soft Tissue Sarcoma Cells Are Highly Sensitive to AKT Blockade: A Role for p53-Independent Up-regulation of GADD45α

“…Immunohistochemistry was performed as previously described (27). Briefly, paraffin sections were dewaxed and rehydrated before antigen retrieval.…”

Novel SN-38–Incorporated Polymeric Micelle, NK012, Strongly Suppresses Renal Cancer Progression

“…The clinical importance of angiogenesis in human tumors has been shown in several reports indicating a positive relationship between the blood vessel density in the tumor mass and poor prognosis with chemoresistance in patients with various cancers (7)(8)(9). Furthermore, recent reports showing that anticancer agents were less active against VEGF-overexpressing tumors (10,11) may support the idea that low-molecular drugs are not so effective in the treatment of solid tumors which are rich in blood vessels.…”