Giatromanolaki A, Koukourakis M I, Stathopoulos G P, Kapsoritakis A, Paspatis G, Kakolyris S, Sivridis E, Georgoulias V, Harris A L, Gatter K C
Tumour and Angiogenesis Research Group, Iraklion, Crete, Greece.
Oncol Res. 2000;12(1):33-41. doi: 10.3727/000000001108747426.
The assessment of the angiogenic profile of tumors may become an important tool as a guide for the inclusion of novel drugs and molecular therapies into the standard chemoradiotherapy policy. Several studies have shown the prognostic importance of microvessel density (MVD) and of angiogenic factor expression in operable gastric cancer. In the present study we investigated, with immunohistochemistry the MVD, the expression of vascular endothelial growth factor (VEGF) and of thymidine phosphorylase (TP) expression, as well as the nuclear expression of p53 protein, in a series of patients with locally advanced inoperable gastric cancer. A strong association of VEGF with TP expression was noted (P = 0.005), and tumors coexpressing these factors had a statistically higher MVD (P = 0.0001). Nuclear p53 accumulation was also related to a high MVD (P = 0.004), and this was independent of VEGF or TP expression. Microvessel density showed a bell-shaped association with prognosis; cases with an intermediate MVD exhibit a favorable outcome (P < 0.05). A trend of nuclear TP expression to define a group of patients with poorer prognosis was noted (P = 0.06), while none of the remaining variables showed any significant association. The immunostaining results allowed the grouping of the angiogenic profile in four major categories: 1) highly vascularized tumors with VEGF and/or TP expression (about 36% of cases); 2) highly angiogenic tumors with p53 nuclear accumulation and low VEGF/TP expression (7% of cases); 3) poorly vascularized tumor with low VEGF/TP and negative nuclear p53 staining (32% of cases); 4) poorly vascularized tumors with TP expression (7% of cases). Specific therapies targeting hypoxia, VEGF, or TP expression as well as p53 gene therapy have entered clinical experimentation or are already available for clinical use. Using the suggested markers more than 80% of locally advanced gastric carcinomas can be grouped in different categories according to their angiogenic profile. Such a categorization may be useful for phase III trials on novel therapies targeting the major angiogenesis-related features studied here.
评估肿瘤血管生成特征可能成为一项重要工具，作为将新型药物和分子疗法纳入标准放化疗策略的指导。多项研究表明微血管密度（MVD）和血管生成因子表达在可手术胃癌中的预后重要性。在本研究中，我们采用免疫组织化学方法，对一系列局部晚期不可手术胃癌患者的MVD、血管内皮生长因子（VEGF）和胸苷磷酸化酶（TP）的表达以及p53蛋白的核表达进行了研究。结果发现VEGF与TP表达之间存在强关联（P = 0.005），同时表达这些因子的肿瘤在统计学上具有更高的MVD（P = 0.0001）。核p53积累也与高MVD相关（P = 0.004），且这与VEGF或TP表达无关。微血管密度与预后呈钟形关联；MVD处于中等水平的病例预后良好（P < 0.05）。注意到核TP表达有界定一组预后较差患者的趋势（P = 0.06），而其余变量均未显示出任何显著关联。免疫染色结果可将血管生成特征分为四大类：1）具有VEGF和/或TP表达的高血管化肿瘤（约占病例的36%）；2）具有p53核积累且VEGF/TP表达低的高血管生成性肿瘤（7%的病例）；3）VEGF/TP低且核p53染色阴性的低血管化肿瘤（32%的病例）；4）具有TP表达的低血管化肿瘤（7%的病例）。针对缺氧、VEGF或TP表达的特异性疗法以及p53基因疗法已进入临床试验阶段或已可用于临床。使用所建议的标志物，超过80%的局部晚期胃癌可根据其血管生成特征分为不同类别。这种分类对于针对此处研究的主要血管生成相关特征的新型疗法的III期试验可能有用。
