Kamat Aparna A, Merritt William M, Coffey Donna, Lin Yvonne G, Patel Pooja R, Broaddus Russell, Nugent Elizabeth, Han Liz Y, Landen Charles N, Spannuth Whitney A, Lu Chunhua, Coleman Robert L, Gershenson David M, Sood Anil K
Department of Gynecologic Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77230, USA.
Clin Cancer Res. 2007 Dec 15;13(24):7487-95. doi: 10.1158/1078-0432.CCR-07-1017.
Vascular endothelial growth factor (VEGF) is critical for angiogenesis and tumor progression; however, its role in endometrial cancer is not fully known. Therefore, we examined the clinical and therapeutic significance of VEGF in endometrial carcinoma using patient samples and an endometrioid orthotopic mouse model.
Following Institutional Review Board approval, VEGF expression and microvessel density (MVD) counts were evaluated using immunohistochemistry in 111 invasive endometrioid endometrial cancers by two independent investigators. Results were correlated with clinicopathologic characteristics. For the animal model, Ishikawa or Hec-1A cancer cell lines were injected directly into the uterine horn. Therapy experiments with bevacizumab alone or in combination with docetaxel were done and samples were analyzed for markers of angiogenesis and proliferation.
Of 111 endometrial cancers, high expression of VEGF was seen in 56% of tumors. There was a strong correlation between VEGF expression and MVD (P < 0.001). On multivariate analysis, stage (P = 0.04), grade (P = 0.003), VEGF levels (P = 0.03), and MVD (P = 0.037) were independent predictors of shorter disease-specific survival. In the murine model, whereas docetaxel and bevacizumab alone resulted in 61% to 77% tumor growth inhibition over controls, combination therapy had the greatest efficacy (85-97% inhibition over controls; P < 0.01) in both models. In treated tumors, combination therapy significantly reduced MVD counts (50-70% reduction over controls; P < 0.01) and percent proliferation (39% reduction over controls; P < 0.001).
Increased levels of VEGF and angiogenic markers are associated with poor outcome in endometrioid endometrial cancer patients. Using a novel orthotopic model of endometrioid endometrial cancer, we showed that combination of antivascular therapy with docetaxel is highly efficacious and should be considered for future clinical trials.
血管内皮生长因子（VEGF）对血管生成和肿瘤进展至关重要；然而，其在子宫内膜癌中的作用尚不完全清楚。因此，我们使用患者样本和子宫内膜样原位小鼠模型研究了VEGF在子宫内膜癌中的临床和治疗意义。
经机构审查委员会批准，由两名独立研究人员采用免疫组织化学方法对111例浸润性子宫内膜样子宫内膜癌中的VEGF表达和微血管密度（MVD）计数进行评估。结果与临床病理特征相关。对于动物模型，将Ishikawa或Hec-1A癌细胞系直接注射到子宫角。进行了单独使用贝伐单抗或与多西他赛联合使用的治疗实验，并对样本进行了血管生成和增殖标志物分析。
在111例子宫内膜癌中，56%的肿瘤VEGF呈高表达。VEGF表达与MVD之间存在强相关性（P < 0.001）。多因素分析显示，分期（P = 0.04）、分级（P = 0.003）、VEGF水平（P = 0.03）和MVD（P = 0.037）是疾病特异性生存期较短的独立预测因素。在小鼠模型中，单独使用多西他赛和贝伐单抗可使肿瘤生长比对照组抑制61%至77%，联合治疗在两种模型中疗效最佳（比对照组抑制85 - 97%；P < 0.01）。在接受治疗的肿瘤中，联合治疗显著降低了MVD计数（比对照组降低50 - 70%；P < 0.01）和增殖百分比（比对照组降低39%；P < 0.001）。
VEGF和血管生成标志物水平升高与子宫内膜样子宫内膜癌患者的不良预后相关。使用新型子宫内膜样子宫内膜癌原位模型，我们发现抗血管生成治疗与多西他赛联合使用具有高效性，应考虑用于未来的临床试验。
