Thrombospondin-l and-2 in node-negative breast cancer: Correlation with angiogenic factors, p53, cathepsin D, hormone receptors and prognosis
Thrombospondin-l and-2 in node-negative breast cancer: Correlation with angiogenic factors, p53, cathepsin D, hormone receptors and prognosis
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DOI：
10.1159/000055300
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发表时间：
2001-01-01
期刊：
影响因子：
3.5
通讯作者：
Gion, M
中科院分区：
文献类型：
--
作者：
Gasparini, G;Toi, M;Gion, M
目的：血小板反应蛋白（TSP）是一个多基因家族的五个分泌糖蛋白参与调节细胞增殖，粘附和迁移。TSP家族的两个成员，即TSP-1和TSP-2，也是天然存在的血管生成抑制剂。本研究的目的是确定TSP-1和-2测定的预后意义及其与血管生成肽血管内皮生长因子（VEGF）和胸苷磷酸化酶（TP）的相关性，以及与其他生物学和临床病理学特征的研究。研究方法：我们对168例淋巴结阴性乳腺癌患者进行了一系列评估，中位随访期为66个月，未接受辅助治疗。TSP-1和-2的胞质水平在原发性肿瘤中通过市售免疫测定法测定。结果：我们发现，166个受试肿瘤具有可测量的TSP-1和-2蛋白水平（中值5.978，范围0.579-31.410 ng/mg蛋白）。根据斯皮尔曼等级相关系数，TSP-1和TSP-2与肿瘤大小和组织蛋白酶D呈弱负相关，主成分等级相关分析表明TSP-1和TSP-2、VEGF与TP的相关性较差。临床结局的结果通过单变量和多变量[仅用于无复发生存期（RFS）]）考克斯回归模型进行分析。在RFS（p = 0.427）或总生存期（p = 0.069）的单变量分析中，TSP-1和-2不是显著的预后因素。为了研究“血管生成平衡假说”，进行了双变量分析以研究TSP-1和-2与VEGF、TP或p53的相互作用，但所选模型均不包括TSP-1和-2。最后，在RFS的多变量分析中，采用了先前在较大病例系列中定义的基线模型，包括VEGF、TP及其相互作用。其具有高度显著性（p = 0.002，Harrell c统计值为0.703）;但当加入TSP-1和-2时，其贡献可忽略不计（p = 0.731，Harrell c统计值为0.705）。结论：这项研究的结果表明，TSP-1和-2不提供额外的预后贡献的VEGF和TP的联合作用。在一系列淋巴结阴性乳腺癌患者的研究中，血管生成肽VEGF和TP的测定提供了重要的预后信息。相反，TSP-1和-2，潜在的天然存在的血管生成的负调节因子，缺乏预后价值。版权所有（C）2001 S. Karger AG，巴塞尔。
Objective: Thrombospondins (TSPs) are a multigene family of five secreted glycoproteins involved in the regulation of cell proliferation, adhesion and migration. Two members of the TSP family, namely TSP-1 and TSP-2, are also naturally occurring inhibitors of angiogenesis. The aim of the present study was to determine the prognostic significance of the determination of TSP-1 and -2 and their correlation with the angiogenic peptides vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP), as well as with other biological and clinicopathological features investigated. Methods: We evaluated a series of 168 women with node-negative breast cancer with a median follow-up period of 66 months, not treated with adjuvant therapy. The cytosolic levels of TSP-1 and -2 were determined in the primary tumour by a commercially available immunometric assay. Results: We found that 166 tested tumours had measurable levels of TSP-1 and -2 protein (median value 5.978, range 0.579-31.410 ng/mg of protein). On the basis of Spearman's rank correlation coefficient, a weak inverse association of TSP-1 and -2 with tumour size and cathepsin D was found. Moreover, principal component analysis on ranks evidenced a poor association between TSP-1 and -2, VEGF and TP. The results of the clinical outcome were ana lysed by both univariate and multivarlate [for relapse-free survival (RFS) only]) Cox regression models. TSP-1 and -2 were not significant prognostic factors in univariate analysis for either RFS (p = 0.427) or overall survival (p = 0.069). To investigate the 'angiogenic balance hypothesis', bivariate analyses were performed to investigate the interactions of TSP-1 and -2 with VEGF, TP or p53, but none were included in the selected models. Finally, in multivariate analysis for RFS a baseline model, previously defined in a larger case series and inclusive of VEGF, TP and their interaction was adopted. It was highly significant (p = 0.002, Harrell c statistic value of 0.703); but when TSP-1 and -2 were added, their contribution was negligible (p = 0.731, Harrell c statistic value of 0.705). Conclusions: The results of this study suggest that TSP-1 and -2 do not provide additional prognostic contribution to the joint effects of VEGF and TP. In the series of node-negative breast cancer patients investigated, determination of the angiogenic peptides VEGF and TP gave significant prognostic information. On the contrary, TSP-1 and -2, potential naturally occurring negative regulators of angiogenesis, lacked of prognostic value. Copyright (C) 2001 S. Karger AG, Basel.