Solberg Timothy D, Nearman Jessica, Mullins John, Li Sicong, Baranowska-Kortylewicz Janina
University of Nebraska Medical Center, Omaha, NE, USA.
Int J Radiat Oncol Biol Phys. 2008 Nov 1;72(3):918-26. doi: 10.1016/j.ijrobp.2008.06.1925.
To determine the late effects of radiotherapy (RT) on vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR2), and osteopontin (OPN) expression in cancer and stromal cells.
LS174T xenografted athymic mice were used as a tumor model. Radiation was delivered in two equivalent fractionation schemes: 5 x 7 Gy and 1 x 20 Gy, the latter at two dose rates.
Tumor growth arrest was similar in all treatment groups, with the exception of a better response of small-size tumors in the 5 x 7-Gy group. The host VEGF and OPN levels were directly proportional to the tumor doubling time and were independent of the fractionation scheme. The host and cancer cell VEGFR2 levels in tumor were also directly related to the tumor response to RT.
Upregulated VEGFR2 in cancer cells suggest paracrine signaling in the VEGFR2 pathway of cancer cells as the factor contributing to RT failure. The transient activation of the host VEGF/VEGFR2 pathway in tumor supports the model of angiogenic regeneration and suggests that radiation-induced upregulation of VEGF, VEGFR2, and downstream proteins might contribute to RT failure by escalating the rate of vascular repair. Coexpression of host OPN and VEGF, two factors closely associated with angiogenesis, indicate that OPN can serve as a surrogate marker of tumor recovery after RT. Taken together, these results strongly support the notion that to achieve optimal therapeutic outcomes, the scheduling of RT and antiangiogenic therapies will require patient-specific post-treatment monitoring of the VEGF/VEGFR2 pathway and that tumor-associated OPN can serve as an indicator of tumor regrowth.
确定放射治疗（RT）对癌症和基质细胞中血管内皮生长因子（VEGF）、VEGF受体2（VEGFR2）和骨桥蛋白（OPN）表达的晚期影响。
将LS174T异种移植无胸腺小鼠用作肿瘤模型。采用两种等效分割方案进行放疗：5×7 Gy和1×20 Gy，后者采用两种剂量率。
除5×7 Gy组中小尺寸肿瘤反应较好外，所有治疗组的肿瘤生长停滞情况相似。宿主VEGF和OPN水平与肿瘤倍增时间成正比，且与分割方案无关。肿瘤中宿主和癌细胞的VEGFR2水平也与肿瘤对RT的反应直接相关。
癌细胞中VEGFR2上调表明癌细胞VEGFR2途径中的旁分泌信号是导致RT失败的因素。肿瘤中宿主VEGF/VEGFR2途径的短暂激活支持血管生成再生模型，并表明辐射诱导的VEGF、VEGFR2和下游蛋白上调可能通过提高血管修复速率导致RT失败。宿主OPN和VEGF这两个与血管生成密切相关的因子的共表达表明，OPN可作为RT后肿瘤恢复的替代标志物。综上所述，这些结果有力地支持了以下观点：为了实现最佳治疗效果，RT和抗血管生成治疗的方案需要对患者进行VEGF/VEGFR2途径的治疗后个体化监测，并且肿瘤相关OPN可作为肿瘤再生的指标。
