Ceelen W, Boterberg T, Smeets P, Van Damme N, Demetter P, Zwaenepoel O, Cesteleyn L, Houtmeyers P, Peeters M, Pattyn P
Department of Surgery, Ghent University Hospital, Ghent, Belgium.
Br J Cancer. 2007 Mar 12;96(5):692-700. doi: 10.1038/sj.bjc.6603568. Epub 2007 Feb 13.
Recent data suggest that recombinant human erythropoietin (rhEPO) modulates tumour growth and therapy response. The purpose of the present study was to examine the modulation of radiotherapy (RT) effects on tumour microvessels by rhEPO in a rat colorectal cancer model. Before and after 5 x 5 Gy of RT, dynamic contrast-enhanced -magnetic resonance imaging was performed and endothelial permeability surface product (PS), plasma flow (F), and blood volume (V) were modelled. Imaging was combined with pO(2) measurements, analysis of microvessel density, microvessel diameter, microvessel fractal dimension, and expression of vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1 alpha (HIF-1alpha), Bax, and Bcl-2. We found that RT significantly reduced PS and V in control rats, but not in rhEPO-treated rats, whereas F was unaffected by RT. Oxygenation was significantly better in rhEPO-treated animals, and RT induced a heterogeneous reoxygenation in both groups. Microvessel diameter was significantly larger in rhEPO animals, whereas VEGF expression was significantly lower in the rhEPO group. No differences were observed in HIF-1alpha, Bax, or Bcl-2 expression. We conclude that rhEPO results in spatially heterogeneous modulation of RT effects on tumour microvessels. Direct effects of rhEPO on neoplastic endothelium are likely to explain these findings in addition to indirect effects induced by increased oxygenation.
近期数据表明，重组人促红细胞生成素（rhEPO）可调节肿瘤生长及治疗反应。本研究旨在探讨在大鼠结直肠癌模型中，rhEPO对放疗（RT）作用于肿瘤微血管的调节作用。在5×5 Gy放疗前后，进行动态对比增强磁共振成像，并对内皮通透性表面产物（PS）、血浆流量（F）和血容量（V）进行建模。成像结合pO₂测量、微血管密度分析、微血管直径、微血管分形维数以及血管内皮生长因子（VEGF）、缺氧诱导因子-1α（HIF-1α）、Bax和Bcl-2的表达分析。我们发现，放疗显著降低了对照大鼠的PS和V，但在rhEPO治疗的大鼠中未降低，而F不受放疗影响。rhEPO治疗的动物氧合明显更好，放疗在两组中均诱导了异质性再氧合。rhEPO组动物的微血管直径显著更大，而rhEPO组的VEGF表达显著更低。在HIF-1α、Bax或Bcl-2表达方面未观察到差异。我们得出结论，rhEPO导致放疗对肿瘤微血管的作用在空间上产生异质性调节。除了氧合增加所诱导的间接作用外，rhEPO对肿瘤内皮的直接作用可能解释了这些发现。
