Zhang Lianglin, Hannay Jonathan A F, Liu Juehui, Das Parimal, Zhan Maocheng, Nguyen Theresa, Hicklin Daniel J, Yu Dihua, Pollock Raphael E, Lev Dina
Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Cancer Res. 2006 Sep 1;66(17):8770-8. doi: 10.1158/0008-5472.CAN-06-1217.
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.
为了更好地阐明血管内皮生长因子（VEGF）（165）在软组织肉瘤（STS）生长、转移和化疗耐药中的作用，我们构建了稳定转染VEGF（165）的人STS细胞系，以研究VEGF（165）对STS细胞的体外作用以及这些细胞的培养基对人脐血管内皮细胞的作用。使用携带转染细胞系异种移植物的严重联合免疫缺陷小鼠来评估VEGF过表达的作用以及VEGF受体（VEGFR）2抑制对STS生长、转移和对多柔比星反应的影响。VEGF（165）转染的异种移植物形成了血管丰富的肿瘤，潜伏期更短，生长加速，化疗耐药增强，肺转移发生率增加。使用DC101抗VEGFR2单克隆抗体阻断VEGFR2信号增强了多柔比星的化疗反应；这种联合生物化疗抑制了肿瘤生长并减少了肺转移，且无明显毒性。联合治疗减少了微血管数量，同时增加了血管成熟指数。VEGF过表达本身并不影响肉瘤细胞；然而，VEGF转染细胞的条件培养基导致内皮细胞增殖、迁移和化疗耐药增加。添加DC101可诱导内皮细胞对多柔比星敏感，并抑制内皮细胞分泌的基质金属蛋白酶的活性。因此，我们得出结论，VEGF是STS生长和转移的关键决定因素，并且在我们的模型中，STS化疗耐药是由STS细胞与肿瘤相关内皮细胞之间的相互作用诱导的过程。低剂量多柔比星和抗VEGFR2联合使用可中断STS的生长和转移，这是一种攻击与STS相关内皮细胞的策略。未来，这种治疗方法可能有助于在临床明显转移发生之前治疗STS。
